Degradable flexible piezoelectric composite material and preparation method and application thereof

Abstract

The invention provides a degradable flexible piezoelectric composite material and a preparation method and application thereof. The degradable flexible piezoelectric composite material comprises a base body, a plurality of piezoelectric layers and a plurality of piezoelectric layers, wherein the base body is provided with interwoven fibers; the fiber comprises a matrix and crystal particles dispersed on the surface and / or in the matrix, the crystal particles comprise Rauschel salt crystal particles, and at least part of the crystal particles are embedded in the fiber and form protrusions. The degradable flexible piezoelectric composite material disclosed by the invention has a high-voltage response characteristic and good mechanical flexibility, and can form mechanical matching with soft nervous tissues, so that mechanical stimulation of a traditional rigid piezoelectric material to nerves is avoided. Meanwhile, the composite material has excellent biocompatibility and complete degradability, and the material residue risk caused by long-term implantation is avoided.

Description

TECHNICAL FIELD

[0001] The present application relates to a degradable flexible piezoelectric composite material and a preparation method and application thereof, and belongs to the technical field of biomedical materials. BACKGROUND

[0002] In the biomedical field, the research and application of degradable flexible biomaterials are of great significance for achieving precision medicine, reducing surgical trauma and long-term implantation risks. Piezoelectric materials can realize the bidirectional conversion of mechanical energy and electrical energy, and have broad application prospects in the field of bioelectronic interfaces, such as energy harvesting, tissue regeneration, physiological monitoring, etc. However, traditional piezoelectric materials such as lead zirconium titanate, barium titanate, polyvinylidene fluoride and its copolymer, etc. have high piezoelectric properties, but are non-degradable materials, which may cause material residues and chronic inflammatory reactions in the body, and may cause tissue damage and infection risks.

[0003] In recent years, degradable piezoelectric materials have become a research hotspot, and amino acid crystals (such as glycine, alanine), proteins (such as silk, collagen), polysaccharides (such as chitosan, cellulose) and synthetic polymers (such as PLLA) have been widely explored. However, these materials generally have weak piezoelectric properties, and complex structure design is required to meet application requirements. In addition, there is often a contradiction between the mechanical flexibility and piezoelectric properties of the material, and the brittleness caused by high crystallinity limits its adaptability to soft biological tissues.

[0004] Rochelle salt (RS, NaKC4H4O6·4H2O) as an FDA-approved food additive has unique advantages: its molecular structure is non-centrosymmetric, and has a significant piezoelectric response (d 14 2300pm / V), and has degradability and biocompatibility. However, the inherent hygroscopicity and brittleness of Rochelle salt crystals limit their application in traditional electronic devices.

[0005] Therefore, it is an urgent technical problem to develop a degradable flexible piezoelectric composite material with high piezoelectric performance, flexibility and biocompatibility. SUMMARY

[0006] Problems to be solved by the application

[0007] In view of the technical problems existing in the prior art, the present application first provides a degradable flexible piezoelectric composite material. The degradable flexible piezoelectric composite material of the present application has excellent piezoelectric performance, flexibility, biocompatibility and degradability, and can be used for nerve stimulation applications, and can be completely degraded in a body fluid environment after the application ends, without remaining in the body.

[0008] The application also provides a preparation method of the degradable flexible piezoelectric composite material.

[0009] Solution for solving the problem

[0010] [1] A degradable flexible piezoelectric composite material, comprising:

[0011] a matrix having interwoven fibers; and,

[0012] crystal particles dispersed on the surface and / or inside of the matrix, the crystal particles comprising RbSe crystal particles, and,

[0013] at least part of the crystal particles are embedded inside the fibers and form protrusions.

[0014] [2] The degradable flexible piezoelectric composite material according to the above-mentioned [1], wherein the material of the matrix comprises a degradable polymer material, preferably comprises a polylactic acid compound;

[0015] Preferably, the mass ratio of the crystal particles to the degradable polymer material is 1:0.2-2, preferably 1:0.25-0.75.

[0016] [3] The degradable flexible piezoelectric composite material according to the above-mentioned [1] or [2], wherein the diameter of the fiber structure is 1-1000 nm, and the particle size of the crystal particles is 0.5-5 μm.

[0017] [4] The degradable flexible piezoelectric composite material according to any one of the above-mentioned [1]-[3], wherein the effective piezoelectric coefficient of the degradable flexible piezoelectric composite material is 18-50 pC / N, preferably 35-50 pC / N, and the tensile modulus of the degradable flexible piezoelectric composite material is 81-307 MPa.

[0018] [5] A preparation method of the degradable flexible piezoelectric composite material according to any one of the above-mentioned [1]-[4], wherein the preparation method comprises the step of compounding the matrix and the crystal particles.

[0019] Preferably, the preparation method comprises the following steps:

[0020] Grinding RbSe crystals to obtain RbSe crystal particles;

[0021] Mixing the RbSe crystals and the degradable polymer material in a solvent to obtain a spinning solution;

[0022] Electrospinning the spinning solution to obtain a spinning product;

[0023] vertically uniaxially compressing the spun product to obtain a degradable flexible piezoelectric composite material.

[0024] [6] The preparation method of any one of the preceding [5], wherein the grinding comprises adding Rochelle salt crystals, zirconium dioxide grinding balls and an alcohol solvent into a grinding tank, and grinding for 12-36 hours using a ball mill.

[0025] [7] The preparation method of any one of the preceding [5] or [6], wherein the solvent comprises an organic solvent, preferably a mixed solvent of dichloromethane and N,N-dimethylformamide, more preferably, the volume ratio of dichloromethane to N,N-dimethylformamide is 3-5:1.

[0026] The mass-volume ratio of the Rochelle salt crystals to the solvent is 0.05-0.2:10 g / mL;

[0027] The mass-volume ratio of the degradable polymer material to the solvent is 0.2-0.5:10 g / mL.

[0028] [8] The preparation method of any one of the preceding [5]-[7], wherein the process parameters of the electrospinning include one or a combination of two or more of the following conditions: the voltage is 10-30 kV, the syringe propelling speed is 0.01-2 mm / min, the collector rotation speed is 400-5000 rpm, the ambient humidity is 30-50%, and the distance between the collector and the needle tip is 10-20 cm.

[0029] [9] The preparation method of any one of the preceding [5]-[8], wherein the pressure applied for the vertical uniaxial compression is 2-100 kN, preferably 30-100 kN, and the application time is 10-30 s.

[0030]

[10] Use of the degradable flexible piezoelectric composite material of any one of the preceding [1]-[3] for preparing an implant for stimulating nerve cells, preferably the stimulation of nerve cells is performed under ultrasonic driving.

[0031] Effects of the invention

[0032] The degradable flexible piezoelectric composite material of the invention has high piezoelectric response characteristics, and at the same time has good mechanical flexibility, can form mechanical matching with soft nerve tissue, and avoids the mechanical stimulation of traditional rigid piezoelectric materials on nerves. At the same time, the composite material has excellent biocompatibility and complete degradability, avoiding the risk of residual material for long-term implantation.

[0033] The degradable flexible piezoelectric composite material of the application can generate an electric signal under ultrasonic stimulation, simulating the bioelectric microenvironment required for nerve growth. A wireless electric stimulation system can be constructed using its performance: ultrasonic excitation of the material generates an electric signal, which directly acts on nerve cells without the need for implanted electrodes or external power supply, avoiding the risk of wire entanglement and infection of traditional electric stimulation devices. This mode can achieve sustained and non-invasive electric stimulation of nerves, and is particularly suitable for clinical outpatient scenarios.

[0034] The preparation method of the degradable flexible piezoelectric composite material of the application preferably uniformly disperses Rochelle salt crystals in nanofibers through electrospinning and uniaxial compression processes. The preparation method is simple and easy to implement, raw materials are easy to obtain, and is suitable for mass production. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 A preparation flowchart of the degradable flexible piezoelectric composite material in the application is shown.

[0036] Figure 2 SEM images of PLLA / RS nanofibers of Example 1 of the application and the degradable flexible piezoelectric composite material PRSC of Example 1 of the application, and elemental analysis results of the degradable flexible piezoelectric composite material PRSC of Example 1 of the application are shown.

[0037] Figure 3 X-ray diffraction (XRD) patterns of PLLA / RS nanofibers of Example 1 of the application, the degradable flexible piezoelectric composite material PRSC of Example 1 of the application, solvent-cast PLLA / RS nanofibers of Comparative Example 1, PLLA, and Rochelle salt crystals are shown.

[0038] Figure 4 Polar plot analysis of the degradable flexible piezoelectric composite material PRSC of Example 1 of the application and solvent-cast PLLA / RS nanofibers of Comparative Example 1 is shown.

[0039] Figure 5 Morphology comparison of PLLA / RS nanofibers of Examples 1-4 of the application under different Rochelle salt crystal contents is shown.

[0040] Figure 6 Morphology comparison of PLLA / RS nanofibers of Example 1 and Examples 5-6 of the application under different collector rotation speeds is shown.

[0041] Figure 7 d 33eff variation chart of the degradable flexible piezoelectric composite materials PRSC of Example 1, Examples 5-6 of the application under different degrees of orientation (collector rotation speed) is shown.

[0042] Figure 8d of the degradable flexible piezoelectric composite PRSC of Example 1, Examples 7-9 of the present application under different compression forces 33eff Variation graph.

[0043] Figure 9 Stress-strain curves of PLLA / RS nanofibers of Examples 1-4 of the present application and the degradable flexible piezoelectric composite PRSC of Example 1.

[0044] Figure 10 Performance comparison graph of the degradable flexible piezoelectric composite PRSC of Example 1 of the present application and reported flexible piezoelectric materials.

[0045] Figure 11 Live / dead staining flow cytometry detection result graph of SH-SY5Y cells on the surface of the degradable flexible piezoelectric composite PRSC of Example 1 of the present application.

[0046] Figure 12 Degradation image of the degradable flexible piezoelectric composite PRSC of Example 1 of the present application in PBS buffer at 65°C.

[0047] Figure 13 Result graph of the degradable flexible piezoelectric composite PRSC of Example 1 of the present application promoting neurite elongation of spinal cord neuron cells under ultrasonic driving.

[0048] Figure 14 Schematic diagram of the degradable flexible piezoelectric composite PRSC of Example 1 of the present application stimulating nerve cells under ultrasonic driving. DETAILED DESCRIPTION

[0049] Various exemplary embodiments, features, and aspects of the present application will be explained in detail in following with reference to the drawings. The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any implementation described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other implementations.

[0050] In addition, in order to better illustrate the present application, numerous specific details are given in the following detailed description. Those skilled in the art will understand that the present application can be practiced without certain specific details, and the present application is equally applicable to situations of the art without some specific details. In some instances, methods, means, instruments and steps well known to those skilled in the art are not described in detail in order to highlight the principles of the present application.

[0051] Unless otherwise stated, the units used in the present specification are international standard units, and the numerical values and numerical ranges appearing in the present application should be understood to include systematic errors that are inevitable in industrial production.

[0052] In the present specification, the meaning indicated by "may" includes both the meaning of performing the process and the meaning of not performing the process.

[0053] In the present specification, the expressions "some embodiments", "other embodiments", "embodiments", and the like refer to the specific elements (for example, features, structures, properties, and / or characteristics) described in relation to the embodiments and are included in at least one of the embodiments described herein, and can be present in other embodiments or can not be present in other embodiments. In addition, it should be understood that the elements can be combined in various embodiments in any suitable manner.

[0054] In the present specification, the numerical range indicated by "numerical value A-numerical value B" refers to a range including the end point values A, B.

[0055] <First aspect>

[0056] The first aspect of the present application provides a degradable flexible piezoelectric composite material, comprising:

[0057] a matrix having interwoven nanofibers; and,

[0058] crystal particles dispersed on the surface and / or inside of the matrix, the crystal particles comprising Rochelle salt crystal particles, and,

[0059] At least part of the crystal particles are embedded inside the nanofibers and form protrusions.

[0060] The degradable flexible piezoelectric composite material of the present application has high piezoelectric response characteristics, while having good mechanical flexibility, can form a mechanical match with soft nerve tissue, and avoid the mechanical stimulation of traditional rigid piezoelectric materials on nerves. At the same time, the composite material has excellent biocompatibility and complete degradability, avoiding the risk of residual material of long-term implantation.

[0061] In some specific embodiments, the material of the matrix comprises a degradable high molecular material. Specifically, the degradable high molecular material can be a synthetic degradable and biocompatible high molecular material. Specifically, it is a fiber derived from one or more than two combinations of polylactic acid compounds, polyglycolic acid, polycaprolactone, polyglycolide-lactide, polycarbonate, polyamino acid, polyhydroxyaliphatic acid ester, or a copolymer of multiple raw monomers of these polymers. Preferably, it comprises polylactic acid compounds, such as poly-L-lactic acid. The above fibers of the present application have good degradability and biocompatibility, which are beneficial for the preparation of nerve cell stimulating implants.

[0062] In some embodiments, the mass ratio of the crystal particles to the degradable polymer material is 1:0.2-2, preferably 1:0.25-0.75, and more preferably 1:0.25-0.5. When the mass ratio of the crystal particles to the degradable polymer material is 1:0.2-2, at least part of the crystal particles can be embedded in the nanofibers and form protrusions. The inventors of the present application have found that, with the increase of the content of the crystal particles, there are agglomerated crystal particles in the voids outside the fibers. Therefore, in the present application, the mass ratio of the crystal particles to the degradable polymer material is preferably 1:0.25-0.75.

[0063] In the present application, the matrix has nanofibers interwoven with each other. The present application can be prepared by electrospinning the material of the above matrix to obtain continuous fibers. The principle of electrospinning is that, in the electrospinning process, a high voltage is applied to the polymer liquid to introduce electric charges into the liquid. When the electric charges in the liquid reach a certain amount, the liquid will form a Taylor cone at the nozzle, and overcome the surface tension to form a liquid jet under the action of the applied electric field force. Then, under the combined action of the electrostatic repulsion, Coulomb force and surface tension, the polymer jet moves along an irregular spiral trajectory. The jet is drawn in a very short time, and the polymer jet solidifies to form nanofibers as the solvent volatilizes or heat is dissipated. In the electrospinning process, many parameters will affect the final electrospun fibers, and by controlling the process parameters, nanofibers of different sizes, morphologies and structures can be prepared.

[0064] In the present application, there is no special requirement for the electrospinning method as long as the diameter of the prepared fiber meets the requirements, and the electrospinning method commonly used in the art can be used. Specifically, in the present application, the raw materials or polymer materials are dissolved in a suitable solvent to prepare a solution with a certain concentration. The raw material solution is spun into fibers with a diameter of 1-1000 nm by electrospinning technology. The morphology of the fibers can be filamentous, flocculent or membrane-like fiber aggregates.

[0065] In the present application, the crystal particles are dispersed on the surface and / or inside of the matrix, and the crystal particles include Rochelle salt crystal particles. Preferably, the particle size of the crystal particles is 0.5-5 μm. The inventors of the present application have found that, by dispersing Rochelle salt crystals on the surface and / or inside of the matrix, a Rochelle salt-based piezoelectric composite material with high piezoelectricity, flexibility, degradability and biocompatibility can be obtained, thereby solving the problem that Rochelle salt crystals are limited in traditional electronic devices due to their inherent hygroscopicity and brittleness.

[0066] Further, at least part of the crystal particles are embedded inside the nanofiber and form protrusions. Crystal particles are prone to agglomeration due to high specific surface area and surface energy, which affects the dipole orientation and piezoelectric effect of the composite material. In the present application, the crystal particles are filled inside the fiber and form protrusions, which can reduce aggregation, ensure structural uniformity and high piezoelectricity in the vertical direction. Moreover, after compression treatment, the density of the nanofiber and the crystal particles is increased, the out-of-plane orientation degree of the particle dipole is increased, and the vertical high piezoelectricity is significantly improved.

[0067] In some specific embodiments, the effective piezoelectric coefficient of the degradable flexible piezoelectric composite material is 18-50 pC / N, preferably 35-50 pC / N, and the tensile modulus of the degradable flexible piezoelectric composite material is 81-307 MPa.

[0068] <Second aspect>

[0069] The second aspect of the present application provides a preparation method of the degradable flexible piezoelectric composite material according to the first aspect of the present application, which comprises the step of compounding the matrix and the crystal particles.

[0070] In some specific embodiments, the preparation method comprises the following steps:

[0071] The Rochelle salt crystal is ground to obtain Rochelle salt crystal particles;

[0072] The Rochelle salt crystal and the degradable polymer material are mixed in a solvent to obtain a spinning solution;

[0073] The spinning solution is electrospun to obtain a spinning product;

[0074] The spinning product is vertically uniaxially compressed to obtain a degradable flexible piezoelectric composite material.

[0075] The present application preferably uniformly disperses the Rochelle salt crystal in the nanofiber by electrospinning and uniaxial compression process. The preparation method is simple and easy to operate, the raw materials are easy to obtain, and it is suitable for mass production.

[0076] In the present application, a ball mill can be used to grind the Rochelle salt crystal to obtain micron-sized Rochelle salt crystal particles. Specifically, a planetary ball mill can be used to grind the Rochelle salt crystal.

[0077] In some specific embodiments, the grinding comprises adding the Rochelle salt crystal, zirconium dioxide grinding balls and an alcohol solvent into a grinding tank, and using a ball mill to grind for 12-36 hours.

[0078] Further, in order to make the subsequent electrospinning can be effectively carried out, the Rochelle salt crystal particles can be dried. Specifically, at room temperature for 48 hours or more, so as to facilitate the electrospinning.

[0079] In the present application, the Rochelle salt crystal and degradable polymer material are mixed in a solvent to obtain a spinning solution. The present application does not make special limitations on the composition of the solvent, as long as it can meet the requirements of the subsequent electrospinning process. Typically, the solvent can use common organic solvents, specifically, the organic solvent can be one or more than two combinations of amide solvents, hydrocarbon solvents, halogenated hydrocarbon solvents or fluorine-containing solvents, etc.

[0080] In some specific embodiments, the solvent includes an organic solvent, preferably a mixed solvent including amide solvents and halogenated hydrocarbon solvents, and more preferably a mixed solvent including dichloromethane and N,N-dimethylformamide. By using a mixed solvent of dichloromethane and N,N-dimethylformamide, the ability to quickly volatilize into fibers and certain conductivity can be considered, and the spinning performance can be optimized. More preferably, the volume ratio of dichloromethane to N,N-dimethylformamide is 3-5:1.

[0081] Further, in the present application, the specific concentration of the solvent type for forming the spinning solution is not particularly limited, as long as it can meet the requirements of the subsequent electrospinning process. Specifically, the mass-volume ratio of the Rochelle salt crystal to the solvent is 0.05-0.8:10 g / mL, preferably 0.05-0.4:10 g / mL, and more preferably 0.05-0.3:10 g / mL; the mass-volume ratio of the degradable polymer material to the solvent is 0.2-0.5:10 g / mL.

[0082] In some specific embodiments, the Rochelle salt crystal can be first dispersed in the solvent, and then mixed with the degradable polymer material. During the mixing process, the Rochelle salt crystal and the degradable polymer material can be mixed more uniformly by means of vigorous stirring. The present application does not make special limitations on the time of vigorous stirring, which can generally be 6-18 hours. In addition, the Rochelle salt crystal can be dispersed in the solvent by means of stirring and / or ultrasonic.

[0083] Further, the spinning solution is electrospun to obtain a spinning product. In the present application, the raw material solution is spun into a fibrous, flocculent or membrane-shaped fiber aggregate with a fiber diameter of 1-1000 nm by electrospinning technology. During the electrospinning process, the desired fiber or fiber aggregate, preferably a fiber membrane, can be prepared by adjusting the spinning parameters (such as feed rate, applied voltage and receiving distance, etc.), solution parameters (such as viscosity and surface tension, etc.), receiving tools and spinning environment, etc.

[0084] Further, the electrospinning process can be used to produce the desired spinning product by adjusting the spinning parameters. For example, voltage, syringe advance speed and collector rotation speed, spinning environment, etc. Preferably, the electrospinning process parameters in the present application can be: voltage 10-30 kV, syringe advance speed 0.01-2 mm / min, collector rotation speed 400-5000 rpm, preferably 2000-5000 rpm, ambient humidity 30-50%, and the distance between the collector and the needle tip is 10-20 cm. In the present application, the electrospinning process can use a 13-gauge needle, a 14-gauge needle, a 15-gauge needle, or any other available needle.

[0085] Finally, the spinning product is subjected to vertical uniaxial compression to obtain a degradable flexible piezoelectric composite material. The inventors of the present application have found that by using uniaxial compression, the out-of-plane orientation of each crystal plane of the Rochelle salt crystals in the composite material can be further enhanced, thereby improving the vertical piezoelectric coefficient of the composite material.

[0086] In some specific embodiments, the pressure applied to the vertical uniaxial compression is 2-100 kN, preferably 20-100 kN, more preferably 30-100 kN, and further preferably 30-60 kN, and the time of application is 10-30 s. Specifically, a hydraulic press can be used to uniaxially compress the spinning product at a pressure of 2-100 kN, and a degradable flexible piezoelectric composite material is obtained after holding the pressure for 10-30 s.

[0087] <Third aspect>

[0088] The third aspect of the present application provides a use of a degradable flexible piezoelectric composite material according to the first aspect of the present application for preparing an implant for stimulating nerve cells, preferably, the stimulation of nerve cells is carried out under the driving of ultrasound.

[0089] The degradable flexible piezoelectric composite material of the present application can generate an electric signal under the stimulation of ultrasound, simulating the biological electric microenvironment required for nerve growth. Its performance can be used to construct a wireless electric stimulation system: the material generates an electric signal under the excitation of ultrasound in vitro, which directly acts on nerve cells without the need for implanted electrodes or external power supply, avoiding the risk of wire entanglement and infection of traditional electric stimulation equipment. This mode can achieve sustained and non-invasive electric stimulation of nerves, and is especially suitable for clinical outpatient scenarios.

[0090] Examples

[0091] Embodiments of the present application will be described in detail below with reference to Examples, but those skilled in the art will understand that the following Examples are for illustrative purposes only and should not be construed as limiting the scope of the present application. Where specific conditions are not specified in the Examples, they are carried out under conventional conditions or conditions recommended by the manufacturer. Where the manufacturer of the reagent or instrument used is not specified, it is a conventional product that can be obtained on the market.

[0092] Example 1

[0093] S1: Preparation of rochelle salt (RS) crystal particles

[0094] 10 g of RS crystals, 50 g of zirconium dioxide grinding balls, and 50 mL of ethanol were added to a nylon ball mill tank, and a QM-3SP2 planetary ball mill was used to grind at a speed of 300 rpm for 24 hours. After removing the grinding balls through a filter screen, a mixed solution of RS crystal particles and ethanol was obtained. The mixed solution was dried at room temperature for 48 hours or more to obtain micron-sized RS crystal particles.

[0095] S2: Preparation of PLLA / RS nanofiber

[0096] 0.1 g of micron-sized RS crystal particles were added to a mixed solvent of 8 mL of anhydrous dichloromethane and 2 mL of anhydrous N,N-dimethylformamide, and after stirring for 5 minutes, 0.4 g of PLLA was added and the stirring was continued overnight to obtain a PLLA / RS spinning solution. Under the condition that the ambient humidity was 40% ± 10%, a 15 gauge (1.4 mm inner diameter) needle was used to electrospun the PLLA / RS spinning solution at a flow rate of 0.08 mL / min. The aluminum drum collector was set at a distance of 10 cm from the tip of the needle, the collector was rotated at a speed of 2800 rpm, and a voltage of 28 kV was applied to collect the PLLA / RS nanofiber, which was denoted as PLLA / RS (4:1).

[0097] S3: Uniaxial compression

[0098] The PLLA / RS nanofiber was uniaxially compressed using a hydraulic press at a pressure of 30 kN, and a degradable flexible piezoelectric composite PRSC was obtained after pressure holding for 1 minute.

[0099] Example 2

[0100] The difference from Example 1 is only that 0.2 g of micron-sized RS crystal particles were used to prepare the PLLA / RS nanofiber, and a 14 gauge (1.6 mm inner diameter) needle was used to electrospun the PLLA / RS spinning solution at a flow rate of 0.08 mL / min. The remaining conditions were exactly the same as in Example 1, and the PLLA / RS nanofiber was collected, denoted as PLLA / RS (4:2), and a degradable flexible piezoelectric composite PRSC was prepared.

[0101] Example 3

[0102] The difference between Example 1 and Example 3 is that 0.4 g of micrometer-sized RS crystal particles are used to prepare the PLLA / RS nanofiber, and a 14-gauge needle (1.6 mm inner diameter) is used to electrospin the PLLA / RS spinning solution at a flow rate of 0.08 mL / min. The rest of the conditions are exactly the same as in Example 1, and the PLLA / RS nanofiber is collected and recorded as PLLA / RS (4:4), and the degradable flexible piezoelectric composite PRSC is prepared.

[0103] Example 4

[0104] The difference between Example 1 and Example 4 is that 0.8 g of micrometer-sized RS crystal particles are used to prepare the PLLA / RS nanofiber, and a 13-gauge (1.9 mm inner diameter) needle is used to electrospin the PLLA / RS spinning solution at a flow rate of 0.08 mL / min. The rest of the conditions are exactly the same as in Example 1, and the PLLA / RS nanofiber is collected and recorded as PLLA / RS (4:8), and the degradable flexible piezoelectric composite PRSC is prepared.

[0105] Example 5

[0106] The difference between Example 1 and Example 5 is that the collector rotation speed during electrospinning is 400 rpm. The rest of the conditions are exactly the same as in Example 1, and the PLLA / RS nanofiber is collected and recorded as PLLA / RS (400 rpm), and the degradable flexible piezoelectric composite PRSC is prepared.

[0107] Example 6

[0108] The difference between Example 1 and Example 6 is that the collector rotation speed during electrospinning is 1000 rpm. The rest of the conditions are exactly the same as in Example 1, and the PLLA / RS nanofiber is collected and recorded as PLLA / RS (1000 rpm), and the degradable flexible piezoelectric composite PRSC is prepared.

[0109] Example 7

[0110] The difference between Example 1 and Example 7 is that a hydraulic press is used to uniaxially compress the PLLA / RS nanofiber at a pressure of 2 kN. The rest of the conditions are exactly the same as in Example 1, and the PLLA / RS nanofiber is collected and the degradable flexible piezoelectric composite PRSC is prepared.

[0111] Example 8

[0112] The difference from Example 1 is only that the PLLA / RS nanofiber is uniaxially compressed by a hydraulic machine at a pressure of 50 kN, and the rest of the conditions are exactly the same as in Example 1. The PLLA / RS nanofiber is collected, and the degradable flexible piezoelectric composite PRSC is prepared.

[0113] Example 9

[0114] The difference from Example 1 is only that the PLLA / RS nanofiber is uniaxially compressed by a hydraulic machine at a pressure of 100 kN, and the rest of the conditions are exactly the same as in Example 1. The PLLA / RS nanofiber is collected, and the degradable flexible piezoelectric composite PRSC is prepared.

[0115] Comparative Example 1

[0116] The PLLA / RS composite material is prepared by solvent casting method, and the specific steps are as follows:

[0117] S1: Preparation of rochelle salt (RS) crystal particles;

[0118] 10 g of RS crystals, 50 g of zirconium dioxide grinding balls and 50 mL of ethanol were added to a nylon ball mill tank, and a QM-3SP2 planetary ball mill was used to grind at a speed of 300 rpm for 24 hours. After removing the grinding balls through a filter screen, a mixed solution of RS crystal particles and ethanol was obtained. The mixed solution was dried at room temperature for more than 48 hours to obtain micron-sized RS crystal particles.

[0119] S2: Preparation of PLLA / RS mixed solution

[0120] 0.1 g of micron-sized RS crystal particles was added to a mixed solvent of 8 mL of anhydrous dichloromethane and 2 mL of anhydrous N,N-dimethylformamide, and after stirring for 5 minutes, 0.4 g of PLLA was added, and the stirring was continued overnight to obtain a PLLA / RS mixed solution.

[0121] S3: Solvent evaporation

[0122] The PLLA / RS mixed solution was poured into a polytetrafluoroethylene mold, and was left to stand at a temperature of about 5℃ for 24 hours to allow the solvent to evaporate naturally.

[0123] S4: Drying

[0124] After the solvent was completely evaporated, the shaped material was taken out of the mold, and was dried at room temperature for more than 24 hours to remove the residual solvent, to obtain a PLLA / RS composite material prepared by solvent casting method.

[0125] Performance test

[0126] 1. Physical property characterization

[0127] 1.1 PLLA / RS (4:1) nanofibers of Example 1 and the degradable flexible piezoelectric composite PRSC of Example 1 were observed using a scanning electron microscope, and elemental analysis of the degradable flexible piezoelectric composite PRSC was performed using and X-ray energy dispersive spectroscopy (EDS), and the results are shown in Figure 2

[0128] Figure 2 SEM images of PLLA / RS (4:1) nanofibers of Example 1 (before compression) and the degradable flexible piezoelectric composite PRSC of Example 1 (after compression) and the elemental analysis results of the degradable flexible piezoelectric composite PRSC of Example 1 are shown. It can be seen from Figure 2 that the Rochelle salt crystals are embedded inside the orderly arranged poly-L-lactic acid fibers and form protrusions. The EDS analysis confirms the presence of Rochelle salt crystals through the distribution of characteristic elements sodium (Na) and potassium (K).

[0129] 1.2 The microstructure of PLLA / RS (4:1) nanofibers of Example 1, the degradable flexible piezoelectric composite PRSC of Example 1, solvent-cast PLLA / RS nanofibers of Comparative Example 1, PLLA, and Rochelle salt crystals were characterized using X-ray diffraction, and the results are shown in Figure 3

[0130] Comparing the patterns with the International Centre for Diffraction Data (ICDD) database confirms the presence of diffraction peaks of multiple RS crystals inside the composite, wherein the out-of-plane main crystal planes of RS crystals in the composite obtained by electrospinning are (310), (320), (321), etc., and the main crystal planes of RS crystals in the solvent-cast PLLA / RS nanofibers of Comparative Example 1 are (331), (132), (321), (031), and (221).

[0131] Further pole figure analysis of the (310) and (321) crystal planes in the composite is shown in Figure 4 It is found that the out-of-plane orientation of each crystal plane in the degradable flexible piezoelectric composite PRSC of Example 1 (after uniaxial compression) is enhanced. In contrast, the out-of-plane orientation of the solvent-cast PLLA / RS nanofibers of Comparative Example 1 does not change significantly before and after compression. It can be seen from Figure 3 and Figure 4 that electrospinning and vertical uniaxial compression induce a preferred out-of-plane crystal orientation (alignment of the crystal normal with the surface normal of the degradable flexible piezoelectric composite).

[0132] 1.3 The morphology of the PLLA / RS nanofibers of Examples 1-4 was compared using a scanning electron microscope, and the results are shown in Figure 5 Figure 5 ​​​As can be seen, PLLA / RS(4:4) and PLLA / RS(4:8) nanofibers contain aggregated RS crystal particles in their external voids, while PLLA / RS(4:1) and PLLA / RS(4:2) contain almost none. To ensure the uniformity of the composite material structure and the consistency of the crystal dipole orientation, a mass ratio of Rochelle salt crystals to biodegradable polymer materials of 1:0.25-0.75 is preferred.

[0133] 1.4 The morphology of PLLA / RS nanofibers in Examples 1 and 5-6 were compared using scanning electron microscopy, and the results are as follows: Figure 6 As shown. From Figure 6 As can be seen, the orientation uniformity of PLLA / RS nanofibers increases with increasing rotational speed. Statistical analysis of the Hermann orientation factor for the three types of fibers also revealed that the PLLA / RS nanofibers obtained at 2800 rpm have the highest degree of orientation.

[0134] 1.5 The piezoelectric properties of the biodegradable flexible piezoelectric composite material PRSC from Examples 1 and 5-9, and the PLLA / RS (4:1) (corresponding to 0 kN) from Example 1 were characterized using quasi-static d 33 The testing instrument (ZJ-3A, SMIC Cloud Technology, China) characterizes the macroscopic piezoelectric coefficient of the composite material. Specifically, the biodegradable flexible piezoelectric composite material PRSC is cut into thin slices of the same size (0.5cm × 0.5cm), placed on the lower probe of the test instrument, and the knob is gently rotated to allow the upper and lower probes to gently clamp the slices. After the reading stabilizes, the macroscopic piezoelectric coefficient value is read. The results are as follows: Figure 7 and Figure 8 As shown.

[0135] Depend on Figure 7 It can be seen that the piezoelectric coefficient of PRSC increases significantly with increasing orientation.

[0136] Depend on Figure 8 It can be seen that in the range of 0-30kN, the piezoelectric properties of the composite material are significantly improved with the increase of compressive force; however, after exceeding 30kN, further increases in load have little effect on the piezoelectric properties.

[0137] 1.6 The tensile modulus of the PLLA / RS nanofibers in Examples 1-4 and the biodegradable flexible piezoelectric composite material PRSC in Example 1 were compared. Specifically, the test samples were cut into monolayer sheets of the same size conforming to ASTM D3822, and the stress-strain relationship was characterized using an electronic universal testing machine. The results are as follows: Figure 9 As shown.

[0138] from Figure 9It can be seen that the degradable flexible piezoelectric composite PRSC and the four groups of PLLA / RS nanofibers all exhibit a low tensile modulus (E = 21-81 MPa), which is well matched with human tissues. After uniaxial compression treatment, the tensile modulus of the PRSC is increased by about 30 MPa compared with the composite fiber before compression, but still has good flexibility, and the breaking strength and ductility are improved. In addition, the tensile modulus of the degradable flexible piezoelectric composite PRSC obtained in Examples 8 and 9 is measured to be 138 and 307 MPa, respectively, and the breaking strength and ductility are further improved.

[0139] In addition, Figure 10 A comparison chart of the performance of the degradable flexible piezoelectric composite PRSC prepared in Examples 1, 8 and 9 with the reported flexible piezoelectric materials is shown. It can be seen that the piezoelectric performance of the degradable flexible piezoelectric composite of the present application is better than that of the existing flexible piezoelectric materials, and has a lower tensile modulus, showing good flexibility.

[0140] 2. Compatibility test

[0141] The biocompatibility of the degradable flexible piezoelectric composite PRSC prepared in Example 1 was verified. SH-SY5Y cells were used to verify the biocompatibility of the composite material. After culture, the cells were seeded on the laminin-coated cell climbing sheet (TCP), PLLA fiber and degradable flexible piezoelectric composite PRSC sample at a density of 400,000 per well (6-well plate). After 24 hours, the cells were treated, and after 7-AAD staining, the survival and death cells were detected by flow cytometry, and the experimental results are shown in Figure 11 .

[0142] From Figure 11 It can be seen that the cell survival rates on the TCP, PLLA fiber and degradable flexible piezoelectric composite PRSC sample are similar, all being 99.3%, which shows that the degradable flexible piezoelectric composite of Example 1 has little effect on cell survival and has good biocompatibility, similar to TCP and PLLA.

[0143] 3. Degradation performance

[0144] The degradable flexible piezoelectric composite PRSC prepared in Example 1 was verified for degradability. The dissolution experiment was carried out in a reagent bottle containing PBS solution, and the reagent bottle was placed in a water bath, and the water bath temperature was 65°C. The PBS solution was replaced every day, and the dissolution of the sample was observed at each stage, and the results are shown in Figure 12 .

[0145] Figure 12Photos showing each stage of the dissolving process of the degradable flexible piezoelectric composite PRSC in PBS solution. The degradable flexible piezoelectric composite completely disappeared at 48 days, indicating that the degradable flexible piezoelectric composite has excellent complete biodegradability.

[0146] 4. Stimulation of neural cells

[0147] The degradable flexible piezoelectric composite PRSC was verified for its electrical stimulation effect by using primary spinal cord neuron (RSpN) cells. After RSpN cells were seeded on the surfaces of three groups of materials (TCP, PLLA and the degradable flexible piezoelectric composite PRSC prepared in Example 1) and continuously cultured for 3 days (ultrasonic stimulation with a duration of 2 min and a stimulation intensity of 1 W / cm 2 , duty cycle 50%) was applied every day), the total length of neurites (axons and dendrites) of each group under different conditions was measured, and the results are shown in Figure 13

[0148] As can be seen from Figure 13 , the results of the TCP group show that ultrasonic treatment alone has no accelerating effect on neurite growth (ultrasound (+): 21.25 ± 4.57 μm; ultrasound (-) 22.3637 ± 1.97 μm). The ultrasound-treated PLLA group promotes neurite extension to 40.98 ± 6.77 μm, and the ultrasound (-) group is 30.85 ± 1.97 μm. The degradable flexible piezoelectric composite group of Example 1 extends to 53.66 ± 7.49 μm, which is better than the ultrasound PLLA group and the ultrasound TCP group, and without ultrasonic stimulation, it is 31.83 ± 2.12 μm, which is not significantly different from the non-ultrasound PLLA group and the non-ultrasound TCP group. The above results prove that the piezoelectric effect excited by ultrasonic waves is the main factor for promoting the elongation of neurites of RSpN cells.

[0149] As can be seen from the above, the degradable flexible piezoelectric composite prepared by the preparation method in the present application can generate sufficient electrical signals to stimulate neuron cells under ultrasonic driving, thereby promoting the elongation of neurites of neural cells. The stimulation principle is shown in Figure 14 , under the action of ultrasonic waves, the electrical signals generated by the composite material can open the voltage-gated calcium ion channel (CAV 3.2) on the cell membrane, promoting the influx of calcium ions.

[0150] It should be noted that although the technical solutions of the present application are described with specific examples, those skilled in the art can understand that the present application should not be limited thereto.

[0151] ​Having described various embodiments of the application, it is to be understood that the above description is meant not to limit and not to encompass all of the possible embodiments covered by the claims. Many modifications and variations of this application can be apparent to those of ordinary skill in the art without departing from the spirit and scope of the described embodiments. It is intended that the scope of the application should only be limited by the appended claims.

Claims

1. A biodegradable flexible piezoelectric composite material, characterized in that, include: A matrix having interwoven fibers; and, Crystal particles dispersed on the surface and / or inside the matrix, the crystal particles including Rochelle salt crystal particles, and, At least some of the crystal particles are embedded inside the fiber and form protrusions.

2. The biodegradable flexible piezoelectric composite material according to claim 1, characterized in that, The matrix material includes biodegradable polymer materials, preferably polylactic acid compounds; Preferably, the mass ratio of the crystal particles to the biodegradable polymer material is 1:0.2-2, and more preferably 1:0.25-0.

75.

3. The biodegradable flexible piezoelectric composite material according to claim 1 or 2, characterized in that, The diameter of the fiber structure is 1 to 1000 nm, and the particle size of the crystal particles is 0.5 to 5 μm.

4. The biodegradable flexible piezoelectric composite material according to any one of claims 1-3, characterized in that, The effective piezoelectric coefficient of the biodegradable flexible piezoelectric composite material is 18-50 pC / N, preferably 35-50 pC / N, and the tensile modulus of the biodegradable flexible piezoelectric composite material is 81-307 MPa.

5. A method for preparing a biodegradable flexible piezoelectric composite material according to any one of claims 1-4, characterized in that, The preparation method includes the step of compositing a matrix and crystal particles; Preferably, the preparation method includes the following steps: The Rochelle salt crystals were ground to obtain Rochelle salt crystal particles; Rochelle salt crystals are mixed with biodegradable polymer materials in a solvent to obtain a spinning solution; Electrospinning was performed on the spinning solution to obtain the spun product; The spun product is subjected to vertical uniaxial compression to obtain a biodegradable flexible piezoelectric composite material.

6. The preparation method according to claim 5, characterized in that, The grinding process involves adding Rochelle salt crystals, zirconium dioxide grinding balls, and an alcohol solvent into a grinding jar and grinding for 12–36 hours using a ball mill.

7. The preparation method according to claim 5 or 6, characterized in that, The solvent includes an organic solvent, preferably a mixed solvent of dichloromethane and N,N-dimethylformamide, and more preferably, the volume ratio of dichloromethane to N,N-dimethylformamide is 3 to 5:

1. The mass-to-volume ratio of the Rochelle salt crystals to the solvent is 0.05–0.2:10 g / mL; The mass-to-volume ratio of the biodegradable polymer to the solvent is 0.2–0.5:10 g / mL.

8. The preparation method according to any one of claims 5-7, characterized in that, The electrospinning process parameters include one or more of the following conditions: voltage of 10-30kV, syringe advance speed of 0.01-2mm / min, collector rotation speed of 400-5000rpm, ambient humidity of 30-50%, and distance between the collector and the needle tip of 10-20cm.

9. The preparation method according to any one of claims 5-8, characterized in that, The pressure applied for the vertical uniaxial compression is 2 to 100 kN, preferably 20 to 100 kN, and the application time is 10 to 30 seconds.

10. Use of a biodegradable flexible piezoelectric composite material according to any one of claims 1-3 for preparing an implant that stimulates nerve cells, preferably, the stimulation of nerve cells is performed under ultrasonic drive.

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