Implantable passive pressure sensor and preparation method thereof

Abstract

The invention discloses an implantable passive pressure sensor and a preparation method thereof. The passive pressure sensor comprises electrode layers, a dielectric layer clamped between the electrode layers and a packaging layer wrapping the electrode layers, the electrode layers are coils made of patterned conductor materials, and the dielectric layer and the packaging layer are both made of silk fibroin films; the method comprises the following steps: dissolving degummed silk in a halide salt-formic acid solution to obtain a regenerated silk fibroin solution, curing the regenerated silk fibroin solution at room temperature to form a silk fibroin gel film, then freeze-drying the silk fibroin gel film to obtain a porous silk fibroin film, and preparing a dielectric layer and a packaging layer by using the porous silk fibroin film. And packaging the patterned conductor material between the dielectric layer and the packaging layer. The silk fibroin is used for preparing the sensing device, the overall degradation rate of the device can be more conveniently regulated and controlled, synchronous degradation of all parts of the device is ensured, short-term monitoring of pressure sensing is achieved, and secondary taking-out operation is not needed after implantation.

Description

Technical Field

[0001] The invention belongs to the field of medical equipment, and in particular relates to an implantable passive pressure sensor and a preparation method thereof. Background Art

[0002] Implantable passive pressure sensors are medical devices that do not require built-in power supplies and can monitor changes in body pressure in real time. After implantation, energy can be provided by external devices through electromagnetic induction, radio frequency coupling or capacitive coupling, and piezoelectric materials or micromechanical structures can be used to sense changes in pressure. It can be applied to medical scenarios that require acute or chronic continuous monitoring of pressure, such as vascular pressure, intracranial pressure, intraocular pressure, joint pressure monitoring, etc. However, traditional implantable devices usually require secondary surgery to remove after completing their functions, which has an adverse effect on medical costs, treatment effects and patient quality of life. Implantable electronic devices that can be degraded and absorbed in the body can achieve natural degradation of electronic devices after completing their intended functions by integrating cutting-edge technologies in materials science, biomedical engineering and electronic engineering. No secondary surgery is required. They can be used for short-term monitoring, drug delivery, tissue engineering and controllable biostimulation, which has important research significance and practical value. For example, researchers reported a flexible pressure sensor made entirely of degradable materials (Nat Biomed Eng 2019, 3, 47-57), which was based on edge field capacitance technology and achieved the measurement of arterial blood flow pressure in the body in contact and non-contact modes. Cut magnesium foil is used as the electrode material, microstructured polyglycerol sebacate is used as the pressure sensitive layer, polylactic acid is used as the dielectric layer, polyoctanedioic acid-citrate is used as the encapsulation layer, and poly(hydroxybutyric acid-hydroxyvaleric acid) copolymer is used as the binder to bond the above layers. Similar to this study, although related studies have verified the effectiveness of passive devices for pressure testing and their absorbability in the in vivo environment, current studies mostly use synthetic polymer materials in a single device, involving many material systems, complex preparation processes, and most devices are flexible structures.

[0003] The layered assembly of multi-material systems has the following obvious disadvantages: 1. The interface between different materials may cause poor compatibility, such as stress concentration, interface reaction or interface degradation, which in turn causes unstable performance of the sensor in the in vivo environment; 2. The synthesis of multiple materials requires a complex preparation process, which increases the difficulty and cost of production; 3. The degradation rates of different materials may be inconsistent, making it difficult to coordinate the degradation time of various parts of the sensor in the body; 4. Different materials may also have different biocompatibility and toxicity characteristics, which may induce immune reactions or other side effects after implantation. The prior art lacks an implantable passive pressure sensor constructed with a single material system as the microstructure layer, dielectric layer and packaging layer. Summary of the invention

[0004] In order to solve the problems existing in the background technology, the purpose of the present invention is to propose an implantable passive pressure sensor and a preparation method thereof. The present invention adopts a single natural polymer material, namely silk fibroin, as a microstructure layer, a dielectric layer and a packaging layer to prepare an implantable passive pressure sensor.

[0005] The technical solution adopted by the present invention is as follows, comprising the following steps:

[0006] 1. An implantable passive pressure sensor:

[0007] like Figure 1 As shown, the sensor includes two electrode layers, a dielectric layer sandwiched between the two electrode layers, and two packaging layers respectively coated outside the two electrode layers; the electrode layer is a resonant coil composed of a patterned conductor material; the dielectric layer is mainly composed of one or more layers of silk fibroin film; the packaging layer adopts silk fibroin film.

[0008] The conductor material of the electrode layer includes one or more of a metal electrode, a metal foil and a conductive polymer material.

[0009] When the electrode layer is a metal electrode prepared by evaporation or magnetron sputtering, the electrode layer is prepared and transferred to the surface of the silk fibroin film in the following manner: first, the metal film is patterned by evaporation or magnetron sputtering to obtain a patterned metal electrode, and then the patterned metal electrode is transferred to the silk fibroin film of the dielectric layer by a thermal transfer method, and finally, the silk fibroin film of the encapsulation layer is bonded to the dielectric layer with the electrode layer on the surface by a hot rolling method, so that the electrode layer is encapsulated between the two layers of silk fibroin film.

[0010] When the electrode layer is a metal foil with a thickness of micrometer level, the electrode layer is prepared and transferred to the surface of the silk fibroin film by the following method: firstly, the metal foil is cut by a plane cutting machine or a laser cutting machine to obtain a patterned metal foil, and then the patterned metal foil is intercalated and encapsulated between the dielectric layer and the silk fibroin film of the encapsulation layer by a hot rolling method;

[0011] When the electrode layer is made of conductive polymer material: the electrode layer is prepared and transferred to the surface of the silk fibroin film in the following manner: first, the wettability of the conductive polymer material solution and the low-viscosity surface is adjusted, and the conductive polymer material is prepared into a patterned conductive polymer film by a coating method, and then the patterned conductive polymer film is transferred to the silk fibroin film of the dielectric layer by a thermal transfer method, and finally the silk fibroin film of the encapsulation layer is bonded to the dielectric layer with the electrode layer on the surface by a hot rolling method, so that the electrode layer is encapsulated between the two layers of silk fibroin film.

[0012] The dielectric layer is mainly composed of one or more layers of porous silk fibroin membranes, and the porous silk fibroin membranes are prepared by freeze-drying a silk fibroin gel membrane.

[0013] The encapsulation layer is made of porous silk fibroin membrane or dense silk fibroin membrane.

[0014] 2. A method for preparing an implantable passive pressure sensor, comprising the following steps:

[0015] Step S1, preparation of dielectric layer and encapsulation layer: dissolving degummed silk in a halide-formic acid solution to obtain a regenerated silk fibroin solution, solidifying the regenerated silk fibroin solution into a silk fibroin gel film at room temperature, and then freeze-drying the silk fibroin gel film to obtain a porous silk fibroin film;

[0016] The halide salt includes one of lithium chloride, lithium bromide and calcium chloride;

[0017] The dielectric layer is mainly composed of one or more layers of porous silk fibroin membranes, and the encapsulation layer is made of silk fibroin gel membrane or porous silk fibroin membrane;

[0018] Step S2: prepare an electrode layer using a patterned conductive material, and encapsulate the prepared electrode layer between the dielectric layer and the encapsulation layer, and a passive pressure sensor is obtained after encapsulation.

[0019] In the step S1, the mass ratio of the degummed silk to the halide-formic acid solution is 8-15wt%; the halide-formic acid solution is mainly obtained by mixing halide and formic acid, and the mass concentration of the halide-formic acid solution is 0.5-8.7wt%.

[0020] In step S2, the conductor material of the electrode layer includes one or more of a metal electrode, a metal foil and a conductive polymer material. The electrode layer is prepared and packaged between the dielectric layer and the packaging layer in the following manner:

[0021] When the electrode layer is a metal electrode prepared by evaporation or magnetron sputtering, the metal film is firstly patterned by evaporation or magnetron sputtering to obtain a patterned metal electrode, and then the patterned metal electrode is transferred to the silk fibroin film of the dielectric layer by a thermal transfer method, and finally the silk fibroin film of the encapsulation layer is bonded to the dielectric layer having the electrode layer on the surface by a hot rolling method, so that the electrode layer is encapsulated between the two layers of silk fibroin films;

[0022] When the electrode layer is made of a metal foil with a thickness of micrometer level: firstly, the metal foil is cut by a plane cutting machine or a laser cutting machine to obtain a patterned metal foil, and then the patterned metal foil is intercalated and encapsulated between the dielectric layer and the silk fibroin film of the encapsulation layer by a hot rolling method;

[0023] When the electrode layer is made of conductive polymer material: first, adjust the wettability of the conductive polymer material solution with the low-viscosity surface, use a coating method to prepare the conductive polymer material into a patterned conductive polymer film, then use a thermal transfer method to transfer the patterned conductive polymer film to the silk fibroin film of the dielectric layer, and finally use a hot rolling method to bond the silk fibroin film of the encapsulation layer to the dielectric layer with the electrode layer on the surface, so that the electrode layer is encapsulated between the two layers of silk fibroin film.

[0024] The porous silk fibroin membrane of the dielectric layer is bonded by a hot rolling method without an auxiliary agent or adhesive. The auxiliary agent is a reagent such as hydrophilic ions that activate protein viscosity, and the adhesive is a glue composed of organic molecules or polymer materials.

[0025] The encapsulation layer is a porous silk fibroin film or a dense silk fibroin film. The encapsulation layer can be bonded with the dielectric layer by hot roller pressing after the resonant coil is thermally transferred, so as to encapsulate the pressure sensor composed of the multi-layer structure.

[0026] The implantable passive pressure sensor can be designed so that all its components can be degraded and absorbed in the body environment without the need for secondary surgery to remove it. Since the silk fibroin film can be stacked, the passive pressure sensor can be flexible or rigid depending on the number of stacked layers. Due to the role of the passive antenna, the sensor can be used not only to detect pressure in the body, but also to monitor its degradation failure process in the body.

[0027] The implantable passive pressure sensor of the present invention comprises: a porous silk fibroin film (dielectric layer), two layers of patterned radio frequency coupled antennas (electrode layers) separated by the porous silk fibroin, and two layers of external silk fibroin films as packaging layers; wherein the electrode layer is made of metal or conductive polymer by cutting, engraving or photolithography, and is bonded to the surface of the porous silk fibroin film by methods such as thermal transfer; the porous silk fibroin film is made by freeze-drying the silk fibroin gel film, and its pore structure can be cyclically deformed under pressure; the porous silk fibroin films can be bonded to each other by a hot rolling method without an additive or adhesive, and can also be bonded to a dense silk fibroin film, so the outer packaging layer can be a porous silk fibroin film. Protein film or dense silk protein film; after the sensor structure is encapsulated, a double-layer RF coupling antenna forms a passive resonant circuit. The sensor consists of two sensing spiral layers and a deformable dielectric layer. The three are stacked together in a sandwich structure. Since the porous silk protein film with a microstructure can cyclically deform under pressure, when pressure is applied, the distance between the spiral layers decreases, resulting in an increase in the effective coupling capacitance, thereby reducing the resonant frequency; the sensor communicates wirelessly with an external antenna through near-field electromagnetic coupling. The external antenna detects the changes in the resonant frequency caused by the sensor by connecting to a vector network analyzer, and converts these changes into readable pressure data.

[0028] In the scheme of the present invention, silk fibroin is used as the microstructure layer, dielectric layer and packaging layer of the passive pressure sensor at the same time, and has consistent and controllable degradability. After implantation in the body, each functional layer has a consistent degradation process and coordinated interface, and no secondary surgery is required for removal. Silk fibroin has excellent biocompatibility and extremely low immunogenicity, and will not cause a strong immune response in the corresponding tissue after implantation. In addition to the general functions of conventional coils, the electrode coil can also be degradable in the human body. For example, it can use metals such as magnesium, molybdenum, and zinc that can be absorbed by the human body. Since the surface of the freeze-dried silk film is quite flat, nano-scale metal films, such as electrode materials such as evaporated or sputtered gold and silver, can be transferred to the surface of the silk protein film. During the degradation process, they can also be absorbed and metabolized by the body without significantly affecting safety. Conductive polymers such as polyethylene dioxythiophene: polystyrene sulfonate PEDOT:PSS, polypyrrole, etc. can also be patterned and transferred to the porous silk protein film, and the excellent biocompatibility of these conductive polymers themselves can be used to prepare fully organic implantable pressure sensors.

[0029] The preparation method of the electrode layer pattern includes: for metal electrodes prepared by evaporation or magnetron sputtering, firstly evaporating or sputtering the metal film on a low-viscosity surface and patterning it, and then transferring the metal electrode pattern to the silk protein dielectric layer by a thermal transfer method; for metal foil with a thickness of micrometer level, firstly patterning it by a plane cutting machine or a laser cutting machine, and then intercalating and encapsulating it inside two layers of silk protein films; for conductive polymer materials, firstly adjusting the wettability of the polymer conductor material solution with the low-viscosity surface, and preparing the conductive polymer film by a coating method, and transferring it to the silk protein dielectric layer by a thermal transfer method after patterning.

[0030] The beneficial effects of the present invention are:

[0031] 1. The present invention uses a single-component material of silk fibroin as the microstructure layer, dielectric layer and packaging layer of the passive pressure sensor to prepare the sensor, which has a very important advantage. The unified material can eliminate interface problems and reduce problems such as stress concentration and interface degradation caused by mismatch between materials.

[0032] 2. The present invention adopts a single material system, which can significantly simplify the manufacturing process and reduce production steps and costs.

[0033] 3. The present invention uses a unified material to more conveniently regulate the degradation rate of the entire device, ensure the synchronous degradation of all parts of the device, realize short-term monitoring of pressure sensing, and do not require secondary removal surgery after implantation;

[0034] 4. The silk fibroin of the present invention has excellent biocompatibility and low immunogenicity, and its degradation products are non-toxic, which can reduce the adverse reactions that may occur after implantation in the body. In addition, as a structural material, silk fibroin can control the number of stacked layers to prepare not only flexible devices but also rigid devices. Since silk fibroin can soften in a humid environment, the sensor can be made into a three-dimensional shape in addition to a planar structure. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 It is a schematic diagram of the structure hierarchy of a passive pressure sensor;

[0036] Figure 2 This is a digital photo of the magnesium coil after being encapsulated in the silk fibroin film;

[0037] Figure 3 are digital photos of the encapsulated magnesium coils and silk fibroin films during enzymatic degradation;

[0038] Figure 4 is the S of the sensor at different pressures 11 Graphs;

[0039] Figure 5is a graph showing the variation of the resonant frequency with the applied pressure over a range of more than 300 kPa;

[0040] Figure 6 It is the cyclic response curve of the pressure sensor at 0kPa and 20kPa;

[0041] Figure 7 Schematic diagram of inserting single-layer and double-layer silver patterns into planar and three-dimensional silk fibroin;

[0042] Figure 8 Digital photos of a single-layer silver pattern transferred onto a porous silk fibroin surface, as well as S 11 Graphs;

[0043] Fig. 9 This is a digital photo of a double-layer silver pattern inserted into the silk protein and transformed into a hemispherical three-dimensional shape, as well as the S 11 Graphs;

[0044] Fig.10 This is a digital photo of the PEDOT:PSS coil after it was transferred to the surface of the silk fibroin structure material;

[0045] Fig.11 It is a diagram showing the forming ability of silk devices using a variety of three-dimensional structured silk protein materials, where a is a diagram showing the forming ability of a variety of typical structures, such as bending enhancement, punching, curling, etc.; b is a diagram showing the forming ability of scanning the bone surface structure and three-dimensionally structuring the silk protein rigid device. DETAILED DESCRIPTION

[0046] In order to make the purpose, technical scheme and advantages of the present application clearer, the present application is further described in detail below in conjunction with the accompanying drawings and examples. It should be understood that the specific embodiments described herein are only used to explain the present application and are not intended to limit the present application. In general, the terms and phrases used herein have the meanings generally recognized in their respective fields, which can be found by reference to standard texts, periodicals or texts known in the art. The following definitions are provided to clarify their specific applications in the text of the present invention.

[0047] "Microstructure layer" refers to a layer with a specific microstructure, which is used to control the physical or chemical properties of the device. In microelectronic devices, these microstructures are usually designed as nano- or micron-scale patterns, grooves or other structural forms to enhance the sensing function or electrical properties of the device. The microstructure layer in this article is silk protein with a porous structure at the nano to micro scale. "Dielectric layer" is an insulating layer located between two conductive electrode layers. It is mainly used to prevent current leakage and allow the formation and transmission of electric fields. It is a key insulating component in microelectronic devices. The "dielectric layer" in this article has a porous structure, so it is also a "microstructure layer". "Electrode layer" is a conductive layer in the device, usually with a patterned lead structure for connection, communication or electromagnetic coupling with an external circuit. The electrode layer in this article is composed of metal or conductive polymer. "Encapsulation layer" is the external protective layer of the device, mainly used to protect internal components, usually made of polymers or composite materials. The encapsulation layer in this article is silk protein, which can be designed to have a dense structure or a porous structure as needed. "Silk fibroin" refers to a structural protein that is a natural fibrous protein produced by certain spiders and insects (such as silkworms). In some embodiments, silk fibroin is obtained from a solution containing dissolved mulberry silk or spider silk. The particular silk fibroin material explicitly exemplified herein is generally prepared from a material spun by mulberry silkworms (bombyx mori). Generally, the cocoons are boiled in an aqueous solution of 0.02M Na2CO3 for ~ 30 minutes, and then thoroughly rinsed with water to remove the sericin to prepare "degummed silk", that is, "undissolved silk fibroin". "Biodegradable" refers to a material or device that can be naturally decomposed into harmless products through biological processes (such as microorganisms, enzymes, etc.). The degradable sensor herein means that the sensor implanted in the body can be naturally decomposed in the body after completing its mission, without the need for secondary surgery to remove it, thereby reducing risks and costs. "Passive sensor" means that no built-in power supply is required, and only external reading equipment functions and obtains information. The passive pressure sensor herein means that the implanted device transmits data through electromagnetic coupling and tests the pressure in the body, and this operation does not require a wired connection.

[0048] like Figure 1 As shown, the sensor includes two electrode layers 2, a dielectric layer 1 sandwiched between the two electrode layers 2, and two packaging layers 3 respectively coated outside the two electrode layers 2; the electrode layer 2 is a resonant coil composed of a patterned conductor material; the dielectric layer 1 is mainly composed of one or more layers of silk fibroin film; the packaging layer 3 adopts silk fibroin film.

[0049] The conductor material of the electrode layer 2 includes one or more of metal electrodes, metal foils and conductive polymer materials.

[0050] When the electrode layer 2 is a metal electrode prepared by evaporation or magnetron sputtering, the electrode layer 2 is prepared and transferred to the surface of the silk fibroin film in the following manner: first, the metal film is patterned by evaporation or magnetron sputtering to obtain a patterned metal electrode, and then the patterned metal electrode is transferred to the silk fibroin film of the dielectric layer 1 by a thermal transfer method. Finally, the silk fibroin film of the encapsulation layer 3 is bonded to the dielectric layer 1 having the electrode layer 2 on the surface by a hot rolling method, thereby encapsulating the electrode layer 2 between the two layers of silk fibroin film.

[0051] When the electrode layer 2 is made of a metal foil with a thickness of micrometers, the electrode layer 2 is prepared and transferred to the surface of the silk fibroin film in the following manner: first, the metal foil is cut by a plane cutting machine or a laser cutting machine to obtain a patterned metal foil, and then the patterned metal foil is intercalated and encapsulated between the dielectric layer 1 and the silk fibroin film of the encapsulation layer 3 by a hot rolling method;

[0052] When the electrode layer 2 is made of conductive polymer material: the electrode layer 2 is prepared and transferred to the surface of the silk fibroin film in the following manner: first, the wettability of the conductive polymer material solution with the low-viscosity surface is adjusted, and the conductive polymer material is prepared into a patterned conductive polymer film by a coating method, and then the patterned conductive polymer film is transferred to the silk fibroin film of the dielectric layer 1 by a thermal transfer method, and finally the silk fibroin film of the encapsulation layer 3 is bonded to the dielectric layer 1 with the electrode layer 2 on the surface by a hot rolling method, so that the electrode layer 2 is encapsulated between the two layers of silk fibroin film.

[0053] The dielectric layer 1 is mainly composed of one or more layers of porous silk fibroin membranes, and the porous silk fibroin membranes are prepared by freeze-drying a silk fibroin gel membrane.

[0054] like Figure 1 As shown, the middle layer of the passive pressure sensor is a porous silk fibroin film with a porous structure, and serves as a dielectric layer 1 to separate the two electrode resonant coils. The electrode layer 2 is transferred to the surface of the porous silk fibroin film by a thermal transfer method. After the transfer is completed, the outer silk fibroin encapsulation film (encapsulation layer) can be bonded to the porous silk fibroin film with the electrode coil on the surface by a hot rolling method again, so that the electrode structure is encapsulated inside the material.

[0055] 1. Preparation of porous silk fibroin membrane:

[0056] Step S1, firstly, 0.48 g of calcium chloride is added into 7.8 ml of formic acid to react, and after the reaction is completed, a calcium chloride-formic acid solution with a concentration of 4.8 wt % is obtained;

[0057] Step S2, taking 1.3 g of degummed silk and dissolving it in the above 6.8 ml of calcium chloride-formic acid solution, and placing it in an ultrasonic cleaning machine for oscillation for 1 hour, and obtaining a regenerated silk fibroin solution after oscillation;

[0058] Step S3, taking a clean PET (polyethylene terephthalate) substrate, using a four-sided preparation device with a thickness of 400 μm to scrape and coat the regenerated silk fibroin solution on the PET substrate, curing the regenerated silk fibroin solution at room temperature to form a silk fibroin gel film, and drying the silk fibroin gel film;

[0059] Step S4, soaking the dried silk fibroin gel film in water for 10 minutes, and then placing the PET substrate with the silk fibroin gel film attached thereto in a vacuum freeze dryer for freeze drying, so that the silk fibroin gel film is frozen at a vacuum degree of 0.05 MPa and a cold trap temperature of -50°C, so that the surface of the silk fibroin gel film is spontaneously nucleated and frozen, and then freeze-dried in situ to obtain a porous silk fibroin film after freeze drying;

[0060] Step S5, peeling off the freeze-dried porous silk fibroin film from the PET substrate by mechanical peeling; the film thickness of the peeled porous silk fibroin film is about 120 μm, and the pore size of the porous silk fibroin film is 200 nm ± 5 μm. According to infrared spectroscopy analysis, the amorphous structure component contained on the surface of the prepared porous silk fibroin film is 50% to 70%.

[0061] Under the action of the PET substrate, the porous silk fibroin film prepared by this method has a flat surface, which is suitable for transferring the patterned electrode structure to the surface while maintaining the connectivity of the electrode pattern. The high proportion of 50% to 70% amorphous components contained on the surface of the material makes it sticky under thermal excitation conditions, and has the potential to prepare multilayer devices by dry transfer. This is also a basic condition necessary to maintain the pore structure during device manufacturing. The opposite example is that the patterned electrode is first prepared on the substrate, and then the silk fibroin solution is poured and peeled off after drying. The patterned electrode can also be transferred to the silk fibroin surface to prepare a functional circuit; however, it is obvious that the casting transfer method cannot obtain a porous structure as a "microstructure layer".

[0062] The dielectric layer 1 is mainly composed of one or more layers of porous silk fibroin membranes stacked together. The stacking method of the multi-layer porous silk fibroin membrane is as follows: the peeled multi-layer porous silk fibroin film is sequentially hot-rolled and bonded and compressed under a temperature condition of 100°C to 200°C to obtain a multi-layer bonded porous silk fibroin membrane.

[0063] The encapsulation layer 3 is made of a porous silk fibroin film or a dense silk fibroin film, and the dense silk fibroin film is a silk fibroin gel film that has not been subjected to freeze-drying treatment.

[0064] 2. Preparation and assembly of electrode resonant coil:

[0065] The electrode layer is prepared and transferred to the surface of the silk fibroin film by the following method: for metal electrodes prepared by evaporation or magnetron sputtering, the metal film is first evaporated or sputtered on a low-viscosity surface and patterned, and then the metal electrode pattern is transferred to the silk fibroin dielectric layer by a thermal transfer method, and the patterning method includes photolithography or laser etching; for metal foil with a thickness of micrometer level, a plane cutting machine or a laser cutting machine is first used to achieve patterning, and then the foil is intercalated and encapsulated inside two layers of silk fibroin films; for conductive polymer materials, the wettability of the polymer conductor material solution and the low-viscosity surface is first adjusted, and a conductive polymer film is prepared by a coating method, and after patterning, it is transferred to the surface of the porous silk fibroin film by a thermal transfer method.

[0066] In the process of assembling the two-layer electrode resonant coil in opposition, there are two design schemes:

[0067] The asymmetric design is adopted, that is, one layer of coils is in a clockwise pattern and the other layer of coils is in a counterclockwise pattern; this scheme has a larger resonant frequency range and a lower resonant frequency, and has less attenuation in the body tissue; at the same time, it can produce a larger S 11 peak, making it more useful for monitoring capacitance changes; however, due to its asymmetry, it requires more precise alignment and assembly during device fabrication.

[0068] A symmetrical design, where both layers of coils are in a clockwise or counterclockwise pattern, is simpler to design and manufacture and less prone to alignment problems. Although the sensitivity is lower than that of an asymmetric design, it still has good resonance performance. The disadvantage is that the resonance frequency is higher, which may cause greater attenuation of wireless signals when transmitted within the body.

[0069] 3. Packaging of pressure sensor:

[0070] The silk fibroin film of the outer encapsulation layer can be a porous silk fibroin film or a dense silk fibroin film as needed. The method for manufacturing a dense silk fibroin film can be based on the method for preparing a porous silk fibroin film, and a dense silk fibroin film can be obtained without freeze drying. Even if the encapsulation layer adopts a porous silk fibroin film, after the pressure sensor is encapsulated, the outer layer can be made dense by a densification operation. In a preferred post-treatment, the silk fibroin-based pressure sensor after multi-layer bonding encapsulation is placed in a constant temperature and humidity chamber with a humidity of 85% RH for 2 hours, and then the silk fibroin block is compressed in the thickness direction under a pressure of 2MPa to achieve densification. Due to the supporting effect of the porous structure, the outer pores collapse preferentially under pressure and absorb energy, and the core layer can maintain a porous structure, thereby still having a pressure sensing function.

[0071] Example 1: Degradable sensor encapsulated with magnesium coil

[0072] Figure 2The digital photo shows the magnesium coil encapsulated inside the silk protein film, and the encapsulated sensor has a flat surface structure. In Example 1, 10U / ml protease E solution was prepared using 0.01M phosphate buffer solution, and the densified silk sheet was subjected to a degradation experiment at 37°C. Figure 3 Digital photos of the degradation process of the sensor in protease E solution are shown. The results show that the porous silk fibroin film is completely degraded after 2 days, and the magnesium coil is completely degraded after 7 days.

[0073] In one embodiment, the pressure sensing performance of the sensor was also monitored. The magnesium antenna adopts an asymmetric structure. Wireless signal measurement is performed using a vector network analyzer and a homemade reading coil (coil diameter 1 cm, copper wire diameter 1 mm). A mechanical testing machine is used to apply pressure to the sensor and record the S of the sensor under different pressures. 11 Curves, such as Figure 4 As shown in the figure. Under the action of pressure, the distance between the magnesium coils decreases, resulting in an increase in the effective coupling capacitance, which reduces the resonant frequency and thus realizes pressure sensing. Figure 5 The peak and valley frequencies under different pressures are continuously recorded. In the range of 0-50 kPa, the sensor sensitivity is -1.46 MHz / kPa. Figure 6 The cyclic response capability of the pressure sensor at 0 kPa and 20 kPa (cycles represents the number of cycles) is shown, which has excellent cyclic response performance, indicating that the porous microstructure can be cyclically deformed under pressure.

[0074] Example 2: Encapsulated silver coil and three-dimensional structure

[0075] In this embodiment, packaging and structuring of the ultra-thin patterned metal structure is also demonstrated. Figure 7 The schematic diagram shows the planar packaging of single-layer silver antenna and double-layer silver antenna, and then the hemispherical three-dimensionalization. First, 50nm of metallic silver was magnetron sputtered on the surface of polydimethylsiloxane, and the coil structure was prepared by infrared laser etching. The metallic silver was transferred to the surface of the porous silk protein film under 200℃ hot rolling conditions and encapsulated. Figure 8 a shows a digital photograph of the metallic silver pattern after transfer, Figure 8 b shows the S of the plane pattern and three-dimensional pattern test 11 Curve. This shows that the ultrathin metal film can be effectively transferred to the surface of the porous silk fibroin membrane and maintain conductivity after transfer and three-dimensionalization. Fig. 9 A shows a digital photo of a two-layer metallic silver pattern transferred, encapsulated and three-dimensionalized into a hemispherical shape. Fig. 9 b shows the S of the plane pattern and three-dimensional pattern test 11The curve shows that after the two-layer coil is packaged, its plane and three-dimensional resonance response is more stable.

[0076] Example 3: Encapsulating Conductive Polymer Coils

[0077] In one embodiment, the conductive polymer structure is encapsulated and designed into a customized structure. First, PEDOT:PSS is used as a conductive material, the wettability of the PEDOT:PSS solution and polydimethylsiloxane is adjusted, and a conductive polymer film is prepared by a coating method, and the PEDOT:PSS film is patterned by a laser etching method, and then transferred to the surface of the porous silk protein film by a thermal transfer method. Fig.10 A digital photo of the PEDOT:PSS coil after transfer before encapsulation is shown. In order to increase the sensitivity of the pressure sensor, the dielectric layer can first be multi-layered to increase its thickness and deformation ability. The multi-layered silk protein structure has a rigid structure. Fig.10 As shown, in a preferred operation, the structure can be punched or cut after softening to make it more suitable for different implantable application scenarios.

[0078] Example 4: Various implantable silk fibroin three-dimensional structures

[0079] In one embodiment, complex plate processing and three-dimensionalization of rigid structures and electronic devices of multi-layer composite silk fibroin are also demonstrated. Fig.11 a shows the three-dimensional structure of silk fibroin prepared based on different punching molds. Preferably, as Fig.11 As shown in b, it can also be designed on demand according to the structural characteristics and needs of the biological tissue interface. It shows excellent structural processing capabilities. It has the potential for use as an implantable device. The present invention can also insert an electrode layer into it according to the characteristics of different three-dimensional structures, so that the structure has a pressure sensing function.

[0080] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. An implantable passive pressure sensor, characterized in that: The invention comprises two electrode layers (2), a dielectric layer (1) sandwiched between the two electrode layers (2), and two packaging layers (3) respectively coated outside the two electrode layers (2); the electrode layer (2) is a resonant coil composed of a patterned conductor material; the dielectric layer (1) is mainly composed of one or more layers of silk fibroin film; and the packaging layer (3) is made of silk fibroin film.

2. The implantable passive pressure sensor according to claim 1, characterized in that: The conductor material of the electrode layer (2) includes one or more of metal electrodes, metal foils and conductive polymer materials.

3. The implantable passive pressure sensor according to claim 2, characterized in that: When the electrode layer (2) is a metal electrode, the electrode layer (2) is prepared and transferred to the surface of the silk fibroin film in the following manner: first, the metal film is patterned by evaporation or magnetron sputtering to obtain a patterned metal electrode, and then the metal electrode is transferred to the silk fibroin film of the dielectric layer (1) by a thermal transfer method, and finally, the silk fibroin film of the encapsulation layer (3) is bonded to the dielectric layer (1) having the electrode layer (2) on its surface, so that the electrode layer (2) is encapsulated between the two layers of silk fibroin film.

4. The implantable passive pressure sensor according to claim 2, characterized in that: When the electrode layer (2) is made of metal foil, the electrode layer (2) is prepared and transferred to the surface of the silk fibroin film in the following manner: first, the metal foil is cut using a plane cutting machine or a laser cutting machine to obtain a patterned metal foil, and then the patterned metal foil is encapsulated between the dielectric layer (1) and the silk fibroin film of the encapsulation layer (3).

5. The implantable passive pressure sensor according to claim 2, characterized in that: When the electrode layer (2) is made of a conductive polymer material, the electrode layer (2) is prepared and transferred to the surface of the silk fibroin film in the following manner: the conductive polymer material is prepared into a patterned conductive polymer film by a coating method, and then the conductive polymer film is transferred to the silk fibroin film of the dielectric layer (1) by a thermal transfer method, and finally the silk fibroin film of the encapsulation layer (3) is bonded to the dielectric layer (1) having the electrode layer (2) on its surface, so that the electrode layer (2) is encapsulated between the two layers of silk fibroin film.

6. The implantable passive pressure sensor according to claim 1, characterized in that: The dielectric layer (1) is mainly composed of one or more layers of porous silk fibroin membrane, and the porous silk fibroin membrane is prepared by freeze-drying a silk fibroin gel membrane.

7. The implantable passive pressure sensor according to claim 1, characterized in that: The encapsulation layer (3) is made of a porous silk fibroin membrane or a dense silk fibroin membrane.

8. A method for preparing an implantable passive pressure sensor according to any one of claims 1 to 7, characterized in that: The following steps are involved: Step S1, preparation of dielectric layer (1) and encapsulation layer (3): dissolving degummed silk in a halide-formic acid solution to obtain a regenerated silk fibroin solution, solidifying the regenerated silk fibroin solution into a silk fibroin gel film at room temperature, and then freeze-drying the silk fibroin gel film to obtain a porous silk fibroin film; The halide salt includes one of lithium chloride, lithium bromide and calcium chloride; The dielectric layer (1) is mainly composed of one or more layers of porous silk fibroin membranes, and the encapsulation layer (3) is made of a silk fibroin gel membrane or a porous silk fibroin membrane; Step S2: using a patterned conductive material to prepare an electrode layer (2), and encapsulating the prepared electrode layer (2) between the dielectric layer (1) and the encapsulation layer (3), and after encapsulation, a passive pressure sensor is obtained.

9. A method for preparing an implantable passive pressure sensor according to claim 8, characterized in that: In the step S1, the mass ratio of the degummed silk to the halide-formic acid solution is 8-15wt%; the halide-formic acid solution is mainly obtained by mixing halide and formic acid, and the mass concentration of the halide-formic acid solution is 0.5-8.7wt%.

10. A method for preparing an implantable passive pressure sensor according to claim 8, characterized in that: In step S2, the conductor material of the electrode layer (2) includes one or more of a metal electrode, a metal foil and a conductive polymer material. The electrode layer (2) is prepared and encapsulated between the dielectric layer (1) and the encapsulation layer (3) in the following manner: When the electrode layer (2) is a metal electrode, the metal film is firstly subjected to evaporation or magnetron sputtering to pattern the metal film to obtain a patterned metal electrode, and then the metal electrode is transferred to the silk fibroin film of the dielectric layer (1) by a thermal transfer method, and finally the silk fibroin film of the encapsulation layer (3) is bonded to the dielectric layer (1) having the electrode layer (2) on its surface, so that the electrode layer (2) is encapsulated between the two layers of silk fibroin film; When the electrode layer (2) is made of metal foil, the metal foil is first cut using a plane cutting machine or a laser cutting machine to obtain a patterned metal foil, and then the patterned metal foil is encapsulated between the dielectric layer (1) and the silk fibroin film of the encapsulation layer (3); When the electrode layer (2) is made of a conductive polymer material, the conductive polymer material is first prepared into a patterned conductive polymer film by a coating method, and then the conductive polymer film is transferred to the silk fibroin film of the dielectric layer (1) by a thermal transfer method. Finally, the silk fibroin film of the encapsulation layer (3) is bonded to the dielectric layer (1) having the electrode layer (2) on its surface, so that the electrode layer (2) is encapsulated between the two layers of silk fibroin film.

Images