Implantable piezoelectric device and manufacturing method thereof

Abstract

The invention provides an implantable piezoelectric device and a manufacturing method thereof. The implantable piezoelectric device comprises a device frame, an upper electrode layer, a lower electrode layer and a piezoelectric sensitive layer. According to the implantable piezoelectric device provided by the invention, the deformation degree of the piezoelectric sensitive material under load force is enhanced by using a dot matrix process, the piezoelectric output performance of the device is improved, and the sensitivity of the device is enhanced; in addition, the W-shaped structural design of the device frame is beneficial to alignment and fixation of layers in the piezoelectric device, and the grooves are formed in the edges of the device frame, so that adhesive filling is facilitated, and the sealing performance of the device is enhanced. The size and thickness of the whole device are reduced under the reasonable structural design, so that the implanted wound area is reduced, the wound infection risk is reduced, and the service life of the device is prolonged. And the device frame adopts an integrated manufacturing process, and large-scale industrialization can be realized. Each part of the implantable piezoelectric device is detachable and supports independent replacement, and the implantable piezoelectric device is high in repeatability and convenient to use.

Description

Technical Field

[0001] The present invention belongs to the technical field of piezoelectric devices, and particularly relates to an implantable piezoelectric device and a manufacturing method thereof. Background Art

[0002] Devices that can implant practical devices into the human body through surgical or non-surgical methods are called implantable devices. They are widely used in the medical field, aiming to treat, monitor, enhance, or replace certain functions of the human body. Currently, implantable devices have evolved from traditional devices such as cardiac pacemakers and artificial joints to complex and high-tech products covering smart devices, sensors, stimulators, neuromodulators, nanogenerators, artificial organs, etc. With the progress of biomedical engineering, implantable devices are gradually trending towards more intelligent, miniaturized, and personalized development.

[0003] The piezoelectric effect refers to the phenomenon that certain materials generate electric charges on their surfaces when subjected to mechanical stress. Conversely, when these materials are subjected to an electric field, they will deform. Implantable piezoelectric devices are usually designed to be able to work stably in the human body for a long time, and achieve various functions such as sensing, energy harvesting, driving, and stimulation through the piezoelectric effect. Due to their miniaturization and the characteristic of not requiring an external power source, piezoelectric devices are particularly suitable for implantable devices in the human body.

[0004] For example, the patent application with the publication number CN114220910A discloses an ultrasonic-driven flexible piezoelectric device for organisms, its preparation and application. This device includes a piezoelectric thin film layer, specifically a composite piezoelectric material doped with inorganic piezoelectric nanomaterials and organic piezoelectric polymers; the inorganic piezoelectric nanomaterials are potassium sodium niobate nanowires, and their surfaces are modified with polydopamine PDA; the organic piezoelectric polymers are at least one of P(VDF-TrFE), PLA, PHBV, PLLA; the piezoelectric thin film layer can generate electromotive force using the piezoelectric effect under ultrasonic action.

[0005] In order to reduce the risk of infection and rejection reaction at the implantation site, the overall material selection of implantable devices tends to bio-organic materials, and their sizes are usually small, thereby reducing the direct contact area between the device and tissues. For example, the patent application with the publication number CN119212542A discloses a bio-piezoelectric thin film with uniform polarization, a preparation method and an application. The bio-piezoelectric thin film includes a substrate layer and a deposition layer on its surface. The substrate layer is made of a conductive material, including low-resistance silicon, ITO conductive glass, or Au / Si; the deposition layer is made of a bio-piezoelectric material, including glycine, polypeptide, protein, or cellulose.

[0006] However, the physical and chemical properties and piezoelectric properties of bioorganic materials are poor, their practicality is weak, and it is difficult to industrialize them; in addition, their small size results in limited effective sensing area and stimulation area of the device, leading to low device sensitivity, poor signal-to-noise ratio, poor stability, and poor overall performance; moreover, there are strict restrictions on the thickness of the device, further affecting the practicality and stability of the device. Summary of the Invention

[0007] To solve the above technical problems existing in the prior art, the present invention provides an implantable piezoelectric device and a manufacturing method thereof. The device structure of the implantable piezoelectric device is designed to enable the piezoelectric device to have excellent biocompatibility and excellent sensitivity, and can effectively meet the diverse needs of the current and future medical fields for implantable piezoelectric devices.

[0008] The present invention provides an implantable piezoelectric device, including a device frame, an upper electrode layer, a lower electrode layer, and a piezoelectric sensitive layer; the device frame includes a first layer, a second layer, a third layer, and a fourth layer that are sequentially connected end to end. The places where the first layer, the second layer, the third layer, and the fourth layer are sequentially connected are connection points. When the device frame is assembled with other components, it is folded into a "W" shape. After the device frame is assembled into the implantable piezoelectric device, the first layer, the second layer, the third layer, and the fourth layer are sequentially stacked together; through holes for installing the piezoelectric sensitive layer are provided on the second layer and the third layer; the upper electrode layer is located between the first layer and the second layer; the lower electrode layer is located between the third layer and the fourth layer; both side surfaces of the piezoelectric sensitive layer are respectively attached to the upper electrode layer and the lower electrode layer; both the upper electrode layer and the lower electrode layer include a carrier layer and a conductive layer, and the conductive layer is located on the side facing the piezoelectric sensitive layer; the carrier layer serves as a support material to resist tensile and compressive loads, and the conductive layer is used for device conduction; the material of the piezoelectric sensitive layer is a bioorganic material, and the materials of the device frame and the carrier layer are both selected from polymer materials and / or bioorganic materials.

[0009] Preferably, a dot matrix protrudes from the surface of the first layer opposite to the second layer, and a dot matrix protrudes from the surface of the fourth layer opposite to the third layer. The positions of the dot matrices correspond to the position of the piezoelectric sensitive layer. The area covered by the dot matrix is smaller than the surface of the piezoelectric sensitive layer attached to the upper electrode layer or the lower electrode layer, or not less than the surface of the piezoelectric sensitive layer attached to the upper electrode layer or the lower electrode layer.

[0010] The dot matrix can enhance the deformation degree of the pressure-sensitive material under the load force, improve the piezoelectric output performance of the piezoelectric device, and enhance the sensitivity of the piezoelectric device. The preparation method of the dot matrix can be a laser cutting method or a patterning method, and the distance between adjacent points in the dot matrix can be uniform or non-uniform.

[0011] Further preferably, the dot matrix is a circular dot matrix, a square dot matrix, a strip dot matrix or a serpentine dot matrix. Further preferably, the dot matrix is an array of cylindrical protrusions, the dot matrix pitch is 20-100 μm, and the dot matrix height is 50-80 μm. Further preferably, the area covered by the dot matrix is not less than the surface where the piezoelectric sensitive layer is attached to the upper electrode layer or the lower electrode layer.

[0012] Preferably, the bio-organic material is selected from one or more of proteins, polypeptides and amino acids. Further preferably, the bio-organic material can be added with modifying groups, and the modifying groups include N-terminal protecting groups and C-terminal protecting groups. The N-terminal protecting groups are selected from one or more of benzyloxycarbonyl, lipid group, tert-butoxycarbonyl and 9-fluorenylmethoxycarbonyl; the C-terminal protecting groups are selected from one or more of nitrobenzyl esters, lipid oxy groups and amide groups.

[0013] Preferably, the polymer material is selected from one or more of polymethyl methacrylate, polydimethylsiloxane, polycarbonate, polyvinyl alcohol, polylactic acid, poly(lactic acid-glycolic acid) copolymer, polycaprolactone, polyethylene, polypropylene and polytetrafluoroethylene. These polymer materials all have excellent biocompatibility, and among them, polyvinyl alcohol, polylactic acid, poly(lactic acid-glycolic acid) copolymer and polycaprolactone also have excellent degradability.

[0014] Even more preferably, the device frame is a film made of a mixture of silk fibroin and glycerol, and the ratio of silk fibroin to glycerol is 8:2.

[0015] Preferably, the length of the device frame before folding is 4-8 cm, the width is 0.5-1 cm, and the thickness is 80-120 μm; the length after folding is 1-2 cm, the width is 0.5-1 cm, and the thickness is 320-480 μm.

[0016] Preferably, the area of the conductive layer is not less than the area of the surface where the piezoelectric sensitive layer is attached to the upper electrode layer or the lower electrode layer. Preferably, the material of the conductive layer is one or more of gold, silver, copper, palladium, aluminum and chromium. Even more preferably, the material of the conductive layer is silver.

[0017] Preferably, the widths of the upper electrode layer and the lower electrode layer are not greater than the width of the device frame before folding, the lengths of the upper electrode layer and the lower electrode layer are less than the length of each layer of the device frame in the folded state, and the thicknesses of the upper electrode layer and the lower electrode layer are 80-120 μm respectively.

[0018] Preferably, the opposite ends of the upper electrode layer and the lower electrode layer to the connection in the device frame serve as the lead-out ends for external detection devices. The lead-out ends are provided with connection parts extending out of the device frame, and the conductive layer extends to the connection parts. The two connection parts on the upper electrode layer and the lower electrode layer are arranged in a staggered manner to prevent the device from short-circuiting due to contact; alternatively, the lead-out ends are provided with wires, and the wires are coated with insulating layers. Further preferably, through holes are provided on the connection parts for winding the leads of the detection devices, which can extend the signal output length of the output end.

[0019] Preferably, two limiting holes are provided at one end close to the connection on the bearing layers of the first layer, the second layer, the third layer, the fourth layer, the upper electrode layer and the lower electrode layer. During use, the implantable piezoelectric device is curled, and the connection parts of the upper electrode layer and the lower electrode layer are respectively passed through one of the limiting holes to meet the requirements of the application scenario where the implantable piezoelectric device needs to be curled for use. Further preferably, the limiting holes are square holes, and the length of the square hole is about 0.2 cm and the width is about 200 μm.

[0020] Preferably, grooves for filling adhesives are provided at the edges of the surfaces of the first layer and the second layer facing the upper electrode layer, the third layer and the fourth layer facing the lower electrode layer, and one of the opposite surfaces of the second layer and the third layer in the device frame for bonding each layer and quickly curing the device, which plays a role in enhancing the sealing performance and ensuring the flatness of the device. Further preferably, the depth of the groove is about 50 - 80 μm. Further preferably, the adhesive is a liquid bio-organic material. The adhesive is more preferably silk fibroin.

[0021] Preferably, a square hollow is provided in the middle of the second layer and the third layer for installing the piezoelectric sensitive layer, and the size of the square hollow depends on the size of the piezoelectric sensitive layer material; further preferably, the square hollow is located at the center of the second layer and the third layer, and the size is 1.0 cm × 0.5 cm.

[0022] The present invention also provides a method for manufacturing the above implantable piezoelectric device, including the following steps:

[0023] S1: Prepare the device frame, the bearing layer of the upper electrode layer, and the bearing layer of the lower electrode layer using polymer materials and / or bio-organic materials;

[0024] S2: Deposit conductive materials on the surfaces of the bearing layer of the upper electrode layer and the bearing layer of the lower electrode layer;

[0025] S3: Fold the device frame into a "W" shape, place the upper electrode layer between the first layer and the second layer, place the lower electrode layer between the third layer and the fourth layer, and seal after alignment;

[0026] S4: Shape it into a piezoelectric sensitive layer using a bio-organic material, and then place the piezoelectric sensitive layer into the cut-out areas of the second and third layers. After sealing, the implantable piezoelectric device is formed.

[0027] Preferably, in step S1, the methods for preparing the device frame, the carrier layer of the upper electrode layer, and the carrier layer of the lower electrode layer are cutting or die casting; in step S2, a conductive material is deposited by evaporation or magnetron sputtering technology.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] (1) The device frame of the implantable piezoelectric device provided by the present invention adopts a "W"-shaped structural design, which is conducive to the alignment and fixation between layers in the piezoelectric device, enhances the sealing performance of the piezoelectric device, and reduces the manufacturing difficulty.

[0030] (2) For the implantable piezoelectric device provided by the present invention, the device frame adopts an integrated manufacturing process, which can be industrialized on a large scale. Each component of the implantable piezoelectric device is detachable and supports individual replacement, with high repeatability and convenient use.

[0031] (3) The implantable piezoelectric device provided by the present invention is prepared from materials with biocompatibility, and the overall device has excellent biological safety. The piezoelectric sensitive material is composed of bio-organic materials and has the property of complete degradation in vivo. The materials of the device frame and the carrier layer can be selected from bio-organic materials or partially biodegradable polymer materials. In this way, the device prepared can be degraded in vivo after completing its function without the need for a second operation to remove it. Or non-biodegradable polymer materials can be selected to monitor the information of the organism for a long time, that is, the biodegradability of the device can be controlled to meet the requirements of different application scenarios. Description of the Drawings

[0032] Figure 1 It is an exploded structural schematic diagram of the implantable piezoelectric device in Example 1;

[0033] Figure 2 It is a front view structural schematic diagram of the implantable piezoelectric device during assembly in Example 1;

[0034] Figure 3 It is a structural schematic diagram of the device frame in Example 1;

[0035] Figure 4 It is a structural schematic diagram of the upper electrode layer or the lower electrode layer in Example 1;

[0036] Figure 5 It is a top view structural schematic diagram of the implantable piezoelectric device after assembly in Example 1;

[0037] Figure 6Positive connection voltage output diagram of the implantable piezoelectric device manufactured in Example 2;

[0038] Figure 7 Negative connection voltage output diagram of the implantable piezoelectric device manufactured in Example 2;

[0039] Figure 8 Load-voltage signal linear relationship diagram of the implantable piezoelectric device manufactured in Example 2;

[0040] Figure 9 Cyclic repeatability test diagram of the implantable piezoelectric device manufactured in Example 2;

[0041] Figure 10 Number of immune cells in the biocompatibility test of the implantable piezoelectric device manufactured in Example 2 in the body of experimental animals, # represents p>0.05, * represents p<0.05, ** represents p<0.01, *** represents p<0.001;

[0042] Figure 11 Average optical proportion diagram of immune cells in the biocompatibility test of the implantable piezoelectric device manufactured in Example 2 in the body of experimental animals;

[0043] Figure 12 Collagen fiber wrapping thickness diagram in the biocompatibility test of the implantable piezoelectric device manufactured in Example 2 in the body of experimental animals;

[0044] Figure 13 Thickness change over time diagram in the biodegradability test of the piezoelectric sensitive layer manufactured according to the method in Example 2 in the body of experimental animals;

[0045] Figure 14 Simulated in-vivo enzyme degradation experiment diagram of the implantable piezoelectric device manufactured in Example 2.

[0046] Reference numerals: device frame 1.1, groove 1.2, lattice 1.3, through hole 1.4, limiting hole 1.5, first layer 1.6, second layer 1.7, third layer 1.8, fourth layer 1.9, upper electrode layer 2.1, lower electrode layer 2.2, through hole 2.3, conductive layer 2.4, bearing layer 2.5, connecting portion 2.6, piezoelectric sensitive layer 3. Detailed implementation manners

[0047] Example 1

[0048] As Figures 1 - 5 shown, this example provides an implantable piezoelectric device, including a device frame 1.1, an upper electrode layer 2.1, a lower electrode layer 2.2, and a piezoelectric sensitive layer 3.

[0049] The device frame includes a first layer 1.6, a second layer 1.7, a third layer 1.8, and a fourth layer 1.9 that are connected end to end in sequence. The places where the first layer 1.6, the second layer 1.7, the third layer 1.8, and the fourth layer 1.9 are connected in sequence are connection points. When the device frame 1.1 is assembled with other components, it is folded into a "W" shape. After the device frame 1.1 is assembled into an implantable piezoelectric device, the first layer 1.6, the second layer 1.7, the third layer 1.8, and the fourth layer 1.9 are stacked together in sequence.

[0050] Before being folded, the device frame 1.1 has a length of 4 - 8 cm, a width of 0.5 - 1 cm, and a thickness of 80 - 120 μm; after being folded, the length is 1 - 2 cm, the width is 0.5 - 1 cm, and the thickness is 320 - 480 μm.

[0051] Through holes 1.4 for mounting the piezoelectric sensitive layer 3 are provided on the second layer 1.7 and the third layer 1.8. The upper electrode layer 2.1 and the lower electrode layer 2.2 are respectively attached to the two side surfaces of the piezoelectric sensitive layer 3.

[0052] The upper electrode layer 2.1 is located between the first layer 1.6 and the second layer 1.7, and the lower electrode layer 2.2 is located between the third layer 1.8 and the fourth layer 1.9.

[0053] The widths of the upper electrode layer 2.1 and the lower electrode layer 2.2 are not greater than the width of the device frame 1.1 before folding. The lengths of the upper electrode layer 2.1 and the lower electrode layer 2.2 are less than the length of each layer of the device frame 1.1 in the folded state. The thicknesses of the upper electrode layer 2.1 and the lower electrode layer 2.2 are respectively 80 - 120 μm.

[0054] In some embodiments, when designing the upper electrode layer 2.1 and the lower electrode layer 2.2, considering that they need to be inserted into the device frame 1.1, their lengths are reduced by 0.2 cm, so that the upper and lower electrode layers are not exposed outside the device frame 1.1.

[0055] Under this device frame 1.1, the electrodes and the bio - organic piezoelectric sensitive material can be replaced arbitrarily to achieve efficient disassembly and replacement of each component. And when the device frame 1.1 is folded into a "W" shape, there are obvious locatable and alignable angles. By using the abutment of these angles, alignment between layers can be achieved.

[0056] Both the upper electrode layer 2.1 and the lower electrode layer 2.2 include a conductive layer 2.4 and a carrier layer 2.5. The carrier layer 2.5 serves as a support material to resist tensile and compressive loads, and the conductive layer 2.4 is used for device conduction.

[0057] The conductive layer 2.4 is located on the side that fits the piezoelectric sensitive layer 3. The area of the conductive layer 2.4 is not less than the area of the side of the piezoelectric sensitive layer 3 that fits the upper electrode layer 2.1 or the lower electrode layer 2.2. The material of the conductive layer 2.4 is one or more of gold, silver, copper, palladium, aluminum, and chromium.

[0058] The material of the piezoelectric sensitive layer 3 is a bio-organic material, and the materials of the device frame 1.1 and the bearing layer 2.5 are both selected from one or more of polymer materials and / or bio-organic materials. The bio-organic material is selected from one or more of proteins, polypeptides, and amino acids. The protein can be selected from β-lactoglobulin and silk fibroin.

[0059] The bio-organic material can be added with modifying groups, and the modifying groups include N-terminal protecting groups and C-terminal protecting groups. The N-terminal protecting groups are selected from one or more of benzyloxycarbonyl, lipid group, tert-butoxycarbonyl, and 9-fluorenylmethoxycarbonyl; the C-terminal protecting groups are selected from one or more of nitrobenzyl esters, lipid oxy groups, and amide groups.

[0060] The polymer material is selected from one or more of polymethyl methacrylate, polydimethylsiloxane, polycarbonate, polyvinyl alcohol, polylactic acid, poly(lactic acid-glycolic acid) copolymer, polycaprolactone, polyethylene, polypropylene, and polytetrafluoroethylene.

[0061] In application scenarios where biodegradable piezoelectric devices are required, the materials of the device frame 1.1 and the bearing layer 2.5 can be selected from proteins, polypeptides, amino acids, polyvinyl alcohol, polylactic acid, poly(lactic acid-glycolic acid) copolymer, or polycaprolactone; in application scenarios where non-biodegradable piezoelectric devices are required, the materials of the device frame 1.1 and the bearing layer 2.5 can be selected from one or more of polymethyl methacrylate, polydimethylsiloxane, polycarbonate, polyethylene, polypropylene, and polytetrafluoroethylene.

[0062] One side of the first layer 1.6 opposite to the second layer 1.7 is convexly provided with a dot matrix 1.3, and one side of the fourth layer 1.9 opposite to the third layer 1.8 is convexly provided with a dot matrix 1.3. The position of the dot matrix 1.3 corresponds to the position of the piezoelectric sensitive layer 3. The area covered by the dot matrix 1.3 is smaller than the surface of the piezoelectric sensitive layer 3 that fits with the upper electrode layer 2.1 or the lower electrode layer 2.2, or not smaller than the surface of the piezoelectric sensitive layer 3 that fits with the upper electrode layer 2.1 or the lower electrode layer 2.2. The dot matrix 1.3 can enhance the degree of deformation of the pressure-sensitive material under the load force and enhance the sensitivity of the piezoelectric device.

[0063] The dot matrix 1.3 can be designed as a circular dot matrix, a square dot matrix, a strip dot matrix, or a snake-shaped dot matrix, and different patterns or shapes are designed to enhance the load strength of the piezoelectric sensitive layer. The preparation method of the dot matrix 1.3 can be a laser cutting method or a patterning method.

[0064] Preferably, the area covered by the dot matrix 1.3 is not smaller than the surface of the piezoelectric sensitive layer 3 that fits with the upper electrode layer 2.1 or the lower electrode layer 2.2 to achieve the best enhancement effect. When the area covered by the dot matrix 1.3 is exactly the surface of the piezoelectric sensitive layer 3 that fits with the upper electrode layer 2.1 or the lower electrode layer 2.2, the performance enhancement effect is the best and the manufacturing cost is relatively low.

[0065] The upper electrode layer 2.1 and the lower electrode layer 2.2 serve as lead-out terminals for external detection devices at one end opposite to the connection part in the device frame 1.1. The lead-out terminals are provided with connection parts 2.6 extending out of the device frame 1.1. The conductive layer 2.4 extends to the connection parts 2.6. The two connection parts 2.6 on the upper electrode layer 2.1 and the lower electrode layer 2.2 are arranged in a staggered manner to prevent the device from short-circuiting due to contact. As Figure 5 shown, from a top-down perspective, it can be observed that the conductive parts of the upper electrode layer 2.1 and the lower electrode layer 2.2 do not intersect.

[0066] Alternatively, the lead-out terminals are provided with wires, and the wires are coated with insulating layers, and they will not contact each other to cause the device to short-circuit. Specifically, liquid silver paste can be used to heat and fix the copper wires on the lead-out terminals of the upper electrode layer 2.1 and the lower electrode layer 2.2, and the exposed copper wires are wrapped with non-conductive outer paint. During testing, the staggered arrangement of the upper and lower electrode layers also facilitates the reverse connection operation.

[0067] The connection part 2.6 is provided with a through hole 2.3 for winding the lead of the detection device, which can extend the signal output length of the output terminal. When the piezoelectric device is implanted into a living body, the connection part 2.6 is exposed outside the epidermis of the living body, and its conductive part does not directly contact the biological tissue.

[0068] At the edges of the side of the first layer 1.6 and the second layer 1.7 facing the upper electrode layer 2.1, the side of the third layer 1.8 and the fourth layer 1.9 facing the lower electrode layer 2.2, and one side of the second layer 1.7 and the third layer 1.8 facing each other in the device frame 1.1, grooves 1.2 for filling the binder are provided, so that the device is encapsulated layer by layer, preventing the slippage between the layers of the piezoelectric device, and playing a role in enhancing the sealing performance and ensuring the flatness of the device. The binder is a liquid bio-organic material, and silk fibroin can be selected.

[0069] In application scenarios where the piezoelectric device needs to be implanted into the body to wrap columnar blood vessels or muscle tissues, etc., the implantable piezoelectric device needs to be curled. In this case, two limiting holes 1.5 can be provided at one end close to the connection part on the bearing layers 2.5 of the first layer 1.6, the second layer 1.7, the third layer 1.8, the fourth layer 1.9, the upper electrode layer 2.1 and the lower electrode layer 2.2. During use, the implantable piezoelectric device is curled, and the connection parts 2.6 of the upper electrode layer 2.1 and the lower electrode layer 2.2 respectively pass through one of the limiting holes 1.5. The first connection part 2.6 and the second connection part 2.6 can pass through the limiting holes 1.5 to form an annular buckle shape, which can further enhance the fastening degree of the upper and lower electrode layers in the device frame 1.1.

[0070] In order to prevent the upper electrode layer 2.1 and the lower electrode layer 2.2 from easily slipping out after being inserted into the angular slots of the device frame 1.1, pattern lines can be added to the surfaces of the device frame 1.1 that come into contact with the upper and lower electrode layers 2.2 to increase the friction and pressing force.

[0071] Example 2

[0072] This embodiment provides a manufacturing method for an implantable piezoelectric device, which specifically includes the following steps:

[0073] S1: Prepare a regenerated silk fibroin (SF) solution from degummed silk fibers. First, perform degumming treatment. The silkworm cocoons are cut into small pieces and boiled in a 0.02M Na 2 CO 3 solution for 30 minutes to remove sericin. Then, the degummed silk is rinsed with deionized water and air-dried overnight in a fume hood. The dried degummed silk fibers are dissolved in a 9.3M LiBr solution, reacted at 60 °C for 4 hours, and then dialyzed for 72 hours to remove salt ions using deionized water. The deionized water is changed every 1 hour, 4 hours, 8 hours, 24 hours, 36 hours, 48 hours, and 60 hours. After dialysis, the solution is purified by two consecutive centrifugations, where the centrifugation speed is 9000 rpm and the duration is 20 minutes. The concentration of the purified silk fibroin solution is approximately 55.0 mg / mL. After the silk fibroin solution is roughly filtered, it is mixed with glycerol in a mass ratio of 8:2 and stirred with a magnetic stirrer for 2 hours. Then, the silk fibroin and glycerol mixed solution (SF-glycerol solution) is added to a special container mold, and the length and width of the mold are 24 cm and 16 cm, respectively. After the solution is fully spread, it is placed in a vacuum drying oven for bubble treatment. Finally, it is placed in the air to dry for 24 hours to form a uniform and transparent film. This SF-glycerol film is the raw material for preparing the device frame, and the film thickness can be adjusted by controlling the amount of solution added to the special container mold. The thickness is maintained at about 100 μm, the film thickness uniformity is high, and the stretchability reaches 150%.

[0074] S2: Preparation of the material for the piezoelectric sensitive layer. First, fibrillate I 3 K. Dissolve the weighed I 3 K powder in deionized water to prepare aqueous solutions with different concentrations. Then, adjust the pH value of the solution to 7.0. Then, seal the solution and perform self-assembly at room temperature for 4 days. Subsequently, utilize the double-network property to prepare a hydrogel with different concentrations of I 3The K aqueous solution and the SF solution with a concentration of 55.0 mg / mL were mixed at a mass ratio of 1:4, and then stirred thoroughly to form a viscous solution. After drying at 40 °C for 10 hours, a supramolecular hydrogel film was obtained. This film was cut into cubes with a width of 0.5 cm, a length of 1 cm, and a thickness of 500 μm. The final pH value of the supramolecular hydrogel film was 6.5, and the hydrogel was semi-transparent and milky white.

[0075] S3: Use laser cutting technology to cut the SF-glycerol film prepared in step S1 to a size of 1 cm × 8 cm. Subsequently, while maintaining the laser power, cut the square hollow and square holes designed on the device frame. After cutting, adjust the laser power, turn it down, and engrave the edge grooves and circular dot protrusions on the inner surface designed on the device frame. Use laser cutting technology to cut out the carrier layer and connection part of the upper and lower electrode layers. The length and width dimensions of the carrier layer are 0.8 cm × 1.8 cm, and the length and width dimensions of the connection part are 0.2 cm × 0.6 cm. In addition, perform hole-opening treatment on the connection part.

[0076] S4: Preparation of the conductive layers of the upper and lower electrode layers. Use the mask method to design and fabricate the conductive paths of the electrodes on the carrier layers and connection parts of the upper and lower electrode layers, and then use magnetron sputtering technology to deposit silver on their surfaces to obtain the conductive layers. The specific steps are as follows: Use the mask plate to perform pattern masking on the carrier layers and connection parts of the upper and lower electrode layers cut in S3. Clamp the carrier layers of the upper and lower electrode layers with a fixture, and place them in the sputtering chamber in a stretched state for sputtering. The sputtered metal is chromium, with a thickness of 10 nm. After the chromium sputtering is completed, perform silver sputtering, with a thickness of 200 nm.

[0077] Considering that the electrodes still need to work after stretching, after the above sputtering is completed, use a fixture to perform silver sputtering on the stretched SF-glycerol film substrate again, with a thickness of about 100 nm. After stretching by 150%, the resistance value of the electrode was calculated, and the resistivity was about 2.6×10 -8 Ω·m.

[0078] S5: Fill the groove of the device frame with liquid silk fibroin as the binder, clamp the upper and lower electrode layers in the upper and lower angles of the device frame, and align them. The first connection part and the second connection part both face the outside of the angle, in a diagonal form, without interfering with each other. After aligning the upper and lower electrode layers in the upper and lower angles, press and seal them, and accelerate the curing of the binder by heating to make them form a whole;

[0079] S6: Fill the square hollow position of the device frame with the piezoelectric sensitive material prepared in step S2, and completely fill the hollow position by extrusion to ensure no voids. Then use liquid silk fibroin for sealing and curing to obtain the implantable piezoelectric device.

[0080] Example 3

[0081] Different from Example 2, in step S2, β-lactoglobulin (βLg) extracted from milk is used as the piezoelectric sensitive material. First, the biological organic protein material β-lactoglobulin is subjected to fiber treatment. The βLg powder is dissolved in deionized water to obtain a 2.0 wt% solution. Then the pH value of the solution is adjusted to 2.0. Then the solution is sealed and allowed to self-assemble in a water bath at 80 °C for 5 hours. Subsequently, βLg aqueous solutions with different concentrations and an SF solution of 55.0 mg / mL are mixed at a mass ratio of 1:4, and then stirred thoroughly to form a viscous solution. It is dried at 45 °C for more than 12 hours to obtain a supramolecular hydrogel film. The final pH value of the supramolecular hydrogel film is 3.5, showing a translucent brown color.

[0082] Example 4

[0083] Different from Example 2, in step S2, a polar polypeptide is used as the piezoelectric sensitive material. First, 9-fluorenylmethoxycarbonyl protected diphenylalanine (Fmoc-FF, CAS: 119350-58-5) is subjected to fibrosis treatment. Specifically, the Fmoc-FF monomer is dissolved in dimethyl sulfoxide to prepare a stock solution of 50 mg / mL. Subsequently, the solution is diluted with deionized water to a final concentration of 5 mg / mL. Fibrosis starts immediately after dilution. Subsequently, the Fmoc-FF self-assembled hydrogel and an SF solution of 55.0 mg / mL are mixed at a mass ratio of 1:5. After thorough mixing, the mixed hydrogel is dried at 40 °C for about 24 hours. Then, the dried gel is soaked in deionized water to form a tough gel. The final pH value of the obtained mixed hydrogel is 4.5, and the hydrogel finally shows an opaque milky white color.

[0084] Detection Example 1

[0085] The forward and reverse connection tests of the piezoelectric voltage output performance of the implantable piezoelectric device prepared in Example 2 are carried out. First, an electrometer is connected to the connection parts of the upper and lower electrode layers of the piezoelectric device, one positive and one negative, and a periodic load is applied by the instrument. The detection result is a periodic waveform output signal, and the voltage amplitude is about 1.6 V. The result is as Figure 6 shown. When the positions of the positive and negative connections of the electrometer are reversed and the same periodic load is also applied, as Figure 7 shown, the detection result is also a periodic waveform output signal, but the waveform direction is opposite to that of Figure 6 , and the absolute value of the voltage amplitude is also about 1.6 V, indicating that its piezoelectric signal has obvious recognition in the forward and reverse connection tests, which can prevent the confusion of forward and reverse connections caused by wire chaos, and can avoid the interference and effect of triboelectricity.

[0086] Detection Example 2

[0087] The fabricated implantable piezoelectric device in Example 2 was tested using an electrometer. By changing the magnitude of the periodic load within the range of 0 - 125 N, the piezoelectric voltage outputs under different loads were collected and a linear graph of piezoelectric voltage versus load was plotted, as Figure 8 shown. The results indicate that the device enhanced by the circular dot array has extremely high linearity and can be used as a sensor, etc. Moreover, its piezoelectric output voltage can reach 3 V, enabling its application in nano piezoelectric generators, etc.

[0088] Detection Example 3

[0089] To achieve test repeatability of the implantable piezoelectric device, pre - stretching and pre - compressing experiments are conducted when the implantable piezoelectric device is officially put into use. The device is subjected to small - range pre - stretching and compression with a small load force to improve the working durability of the device. As Figure 9 shown, the piezoelectric device of Example 2 after pre - stretching and pre - compressing treatment can stably output voltage signals within 2100 s under a fixed load.

[0090] Detection Example 4

[0091] To investigate the overall biocompatibility of the implantable piezoelectric device, a biocompatibility experiment was carried out on the implantable piezoelectric device fabricated in Example 2 (abbreviated as I 3 K / SF - SF, where the piezoelectric sensitive layer material is I 3 K / SF, and the materials of the device frame and the bearing layer are SF - glycerol).

[0092] Twelve I 3 K / SF - SF devices were fabricated according to the manufacturing method of Example 2, and twelve piezoelectric devices I 3 K / SF - PDMS with the same piezoelectric sensitive layer material as in Example 2 and the materials of the device frame and the bearing layer being polydimethylsiloxane were fabricated, as well as twelve piezoelectric devices PVDF - PDMS with the piezoelectric sensitive layer material being polyvinylidene fluoride and the materials of the device frame and the bearing layer being polydimethylsiloxane. The two piezoelectric devices I 3 K / SF - SF and PVDF - PDMS were used as the two control groups in this biocompatibility experiment. PDMS material was selected as a control due to its well - studied biocompatibility, and PVDF was selected as a sensitive material control due to its high piezoelectric performance.

[0093] Twelve I 3 K / SF - SF devices, twelve I 3The K / SF-PDMS device and 12 PVDF-PDMS devices were implanted into 36 experimental rats (SD) one by one for 7-day and 14-day experiments to analyze the biocompatibility of their materials, that is, there were 12 experimental rats implanted with piezoelectric devices in each of the three groups.

[0094] After 7 days of implantation, tissues wrapped with piezoelectric devices were taken out from 6 rats in each group for sectioning. Two sections were taken from each tissue. One section was stained with H&E, and the other was used for subsequent Masson staining. The results of H&E staining are as Figure 10 shown. In the range of 200μm×200μm, the number of inflammatory cells generated by the implantation of the I 3 K / SF-SF device was about 37. In contrast, in the control group I 3 the number of inflammatory cells generated by the implantation of the K / SF-PDMS device was about 45; the number of inflammatory cells generated by the implantation of the control group PVDF-PDMS device was about 145. The experimental results show that the I 3 K / SF-SF device prepared in Example 2 has the best biocompatibility.

[0095] The inflammatory cells in the H&E-stained part of the section were processed by grayscale, and the biocompatibility of the device was illustrated by analyzing the proportion of inflammatory cells in the entire section area. The results are as Figure 11 shown. The proportion of inflammatory cells in the I 3 K / SF-SF device was 1.6%. In the control group I 3 the proportion of inflammatory cells in the K / SF-PDMS device was 1.5%. In the control group PVDF-PDMS device, the proportion of inflammatory cells was 11%. The experimental results show that the device with I 3 K / SF as the piezoelectric sensitive layer material has the best biocompatibility, and there is little difference in the biocompatibility of the devices with PDMS and SF-glycerol as the device frame and bearing layer materials at the 7-day time point.

[0096] The sections were stained with Masson, and the rejection degree of the device was characterized by analyzing the thickness of the stained collagen fibers. The results are as Figure 12 shown. The thickness of the collagen fibers in the I 3 K / SF-SF device was about 70μm. In the control group I 3 the thickness of the collagen fibers in the K / SF-PDMS device was about 58μm. In the control group PVDF-PDMS device, the thickness of the collagen fibers was about 623μm. The experiment shows that when the piezoelectric sensitive layer materials of the piezoelectric devices are the same, the rejection reaction of the SF-glycerol thin film-based device after implantation into experimental rats is not much different from that of the commonly used PDMS-based devices on the market currently. When the piezoelectric sensitive layer material is changed to PVDF, the rejection reaction of the experimental rats is more serious.

[0097] Fourteen days after implantation, the tissues wrapping the piezoelectric devices in the remaining six rats in each group were taken for sectioning and H&E staining. The results are as Figure 10 shown. The number of inflammatory cells generated by the implantation of the I 3 K / SF-SF device was approximately 55. In contrast, the number of inflammatory cells generated by the implantation of the control group I 3 K / SF-PDMS device was approximately 48; the number of inflammatory cells generated by the implantation of the control group PVDF-PDMS device was approximately 320. The experimental results show that 14 days after implantation, I 3 the biocompatibility of the K / SF-SF device and the control group I 3 K / SF-PDMS device was not significantly different from that at 7 days after implantation, while the biocompatibility of the control group PVDF-PDMS device decreased significantly.

[0098] The inflammatory cells in the stained part of the section were processed by grayscale, and the biocompatibility of the device was illustrated by analyzing the proportion of inflammatory cells in the entire section area. The results are as Figure 11 shown. The proportion of inflammatory cells in the I 3 K / SF-SF device was 5%, the proportion of inflammatory cells in the control group I 3 K / SF-PDMS device was 3%, and the proportion of inflammatory cells in the control group PVDF-PDMS device was 20%. The experimental results show that 14 days after implantation, I 3 the biocompatibility of the K / SF-SF device and the control group I 3 K / SF-PDMS device decreased slightly, while the biocompatibility of the control group PVDF-PDMS device decreased significantly.

[0099] The sections were stained with Masson, and the rejection degree of the device was characterized by analyzing the thickness of the stained collagen fibers. The results are as Figure 12 shown. The thickness of the collagen fibers in the I 3 K / SF-SF device was approximately 190 μm, the thickness of the collagen fibers in the control group I 3 K / SF-PDMS device was approximately 244 μm, and the thickness of the collagen fibers in the control group PVDF-PDMS device was approximately 831 μm. The experiment shows that 14 days after implantation, the rejection reactions of all three devices increased compared with those at 7 days after implantation, among which I 3 the K / SF-SF device had the smallest rejection reaction.

[0100] In summary, I 3 the K / SF material and the SF-glycerol material have good biocompatibility, not inferior to commercial PDMS. In addition, I 3 the K / SF-SF device also has excellent biocompatibility and the smallest rejection reaction.

[0101] Detection Example 5

[0102] Twelve piezoelectric sensitive layers with a thickness of 150 μm were prepared according to the method steps of S2 in Example 2, and biodegradability tests were carried out. These twelve piezoelectric sensitive layers were respectively implanted into 12 experimental rats (SD). On the 7th, 14th, 30th, 60th, 90th, and 120th days after implantation, 2 experimental rats were randomly selected for dissection, the piezoelectric sensitive layers were taken out, and the thickness of the piezoelectric sensitive layers was measured. The results are as Figure 13 shown, indicating that this piezoelectric sensitive layer material can be completely degraded within 120 days.

[0103] Six implantable piezoelectric devices I 3 K / SF-SF were prepared according to the manufacturing method of Example 2, and an in vitro enzyme degradation simulation experiment was carried out. Specifically, the six I 3 K / SF-SF devices were respectively immersed in a PBS solution containing 5 U / mL of protease XIV. The piezoelectric devices were taken out every 2 h, dried in an oven at 30 °C for 1 h, weighed, and then put back into the above solution. This operation was repeated until the piezoelectric devices were completely degraded. The results are as Figure 14 shown. The initial mass of the I 3 K / SF-SF device was about 118 mg. The mass of the I 3 K / SF-SF device that was still in shape after 6 h was about 47 mg. After 12 h, the I 3 K / SF-SF device had disintegrated and degraded in the solution, and error bars were formed by 6 groups of repeated experiments. The results show that the implantable piezoelectric device I 3 K / SF-SF can be completely degraded in the in vitro enzyme solution.

Claims

1. An implantable piezoelectric device, characterized in that: It includes a device frame, an upper electrode layer, a lower electrode layer and a piezoelectric sensitive layer; The device frame comprises a first layer, a second layer, a third layer and a fourth layer which are connected end to end in sequence, and the place where the first layer, the second layer, the third layer and the fourth layer are connected in sequence is a connection point; The device frame is folded into a "W" shape when assembled with other components, and after the device frame is assembled into the implantable piezoelectric device, the first layer, the second layer, the third layer and the fourth layer are stacked together in sequence; The second layer and the third layer are provided with through holes for mounting the piezoelectric sensitive layer; The upper electrode layer is located between the first layer and the second layer; the lower electrode layer is located between the third layer and the fourth layer; the two side surfaces of the piezoelectric sensitive layer are respectively attached to the upper electrode layer and the lower electrode layer; The upper electrode layer and the lower electrode layer both include a bearing layer and a conductive layer, and the conductive layer is located on a side that is in contact with the piezoelectric sensitive layer; The material of the piezoelectric sensitive layer is a bio-organic material, and the materials of the device frame and the bearing layer are both polymer materials and / or bio-organic materials.

2. The implantable piezoelectric device according to claim 1, characterized in that: A dot array is convexly provided on one side of the first layer opposite to the second layer, and a dot array is convexly provided on one side of the fourth layer opposite to the third layer, the position of the dot array corresponds to the position of the piezoelectric sensitive layer, and the area covered by the dot array is smaller than the surface where the piezoelectric sensitive layer is bonded to the upper electrode layer or the lower electrode layer, or the area covered by the dot array is not smaller than the surface where the piezoelectric sensitive layer is bonded to the upper electrode layer or the lower electrode layer.

3. The implantable piezoelectric device according to claim 1, characterized in that: The bio-organic material is selected from one or more of proteins, polypeptides and amino acids; The polymer material is selected from one or more of polymethyl methacrylate, polydimethylsiloxane, polycarbonate, polyvinyl alcohol, polylactic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, polyethylene, polypropylene and polytetrafluoroethylene.

4. The implantable piezoelectric device according to claim 1, characterized in that: The device frame has a length of 4-8 cm, a width of 0.5-1 cm and a thickness of 80-120 μm before being folded.

5. The implantable piezoelectric device according to claim 1, characterized in that: The area of ​​the conductive layer is not less than the area of ​​the side to which the piezoelectric sensitive layer is attached, and the material of the conductive layer is one or more of gold, silver, copper, palladium, aluminum and chromium; The width of the upper electrode layer and the lower electrode layer is not greater than the width of the device frame before folding, the length of the upper electrode layer and the lower electrode layer is less than the length of each layer in the folded state of the device frame, and the thickness of the upper electrode layer and the lower electrode layer is 80-120μm respectively.

6. The implantable piezoelectric device according to claim 1, characterized in that: The ends of the upper electrode layer and the lower electrode layer opposite to the connection in the device frame serve as the lead-out terminals for external detection equipment. The lead-out end is provided with a connecting portion and a connecting portion extending out of the device frame, the conductive layer extends to the connecting portion, and the two connecting portions on the upper electrode layer and the lower electrode layer are staggered; Alternatively, the lead end is provided with a wire, and the wire is covered with an insulating layer.

7. The implantable piezoelectric device according to claim 1, characterized in that: Two limiting holes are provided on one end of the supporting layers of the first layer, the second layer, the third layer, the fourth layer, the upper electrode layer and the lower electrode layer near the connection. When in use, the implantable piezoelectric device is curled and the connection part of the upper electrode layer and the lower electrode layer is passed through one of the limiting holes respectively.

8. The implantable piezoelectric device according to claim 1, characterized in that: Grooves for filling adhesive are provided at the edges of the first and second layers of the device frame facing the upper electrode layer, the third and fourth layers facing the lower electrode layer, and one of the sides opposite to the second and third layers.

9. A method for manufacturing an implantable piezoelectric device according to any one of claims 1 to 8, characterized in that: The following steps are involved: S1: using polymer materials and / or bio-organic materials to prepare a device frame, a supporting layer for an upper electrode layer, and a supporting layer for a lower electrode layer; S2: Plating a conductive material on the surface of the carrier layer of the upper electrode layer and the carrier layer of the lower electrode layer; S3: Fold the device frame into a "W" shape, place the upper electrode layer between the first and second layers, place the lower electrode layer between the third and fourth layers, align and seal; S4: Using bio-organic materials to shape a piezoelectric sensitive layer, and then placing the piezoelectric sensitive layer into the hollowed-out portions of the second layer and the third layer, and then sealing to form the implantable piezoelectric device.

10. The manufacturing method according to claim 9, characterized in that: In step S1, the method for preparing the device frame, the upper electrode layer support layer and the lower electrode layer support layer is a cutting method or a mold casting method; In step S2, a conductive material is applied by evaporation or magnetron sputtering technology.

Images