Oral repair membrane and its preparation method

Abstract

This invention provides an oral repair membrane and its preparation method. The oral repair membrane comprises: a substrate, which is formed by interlocking and winding fibers with a diameter of 10 nm-100 μm and has a porous structure; and active particles, which are loaded on the surface and / or inside the substrate, and the active particles are derived from piezoelectric materials and / or hydrophilic polymer materials. The oral repair membrane of this invention has a porous structure with a suitable pore size, which can better shield fibroblasts from growing into the fibrous membrane, avoiding the problem of membrane thickening caused by fibroblast growth. It also has good softness and adhesion, and will not slip during use, avoiding the risk of membrane exposure and reducing the exposure infection rate.

Description

Technical Field

[0001] This invention relates to an oral repair membrane and its preparation method, belonging to the field of medical materials. Background Technology

[0002] GBR (Guided Bone Regeneration) is developed from the biological principle of "guided tissue regeneration" proposed by Dahlin et al. It is based on the theory that "the type of cells that proliferate earliest at the tissue defect site determines the type of wound healing." By placing a guiding bone tissue regeneration barrier membrane between the soft tissue and the bone defect, a biological barrier is artificially created, creating an isolation space. This mechanically prevents soft tissue cells (epithelial cells, fibroblasts, etc.) from migrating and proliferating to the bone defect area, thereby avoiding interference with the osteogenic process in the bone defect area below the membrane. At the same time, the barrier membrane creates and maintains space for bone replacement materials and allows oxygen and nutrients to enter the transplantation site, ultimately achieving complete bone repair in the defect area.

[0003] An ideal barrier membrane should possess the following characteristics: biocompatibility, tissue integration, dimensional stability, operability, selective permeability, and space maintenance. To better meet the performance requirements of GBR membranes, improvements in their fabrication technology are particularly important. Electrospinning is a method for preparing nanofiber membranes using a high-voltage electrostatic field. Electrospinned membranes prepared using this method have certain advantages compared to traditional GBR membranes, such as: this type of membrane possesses a three-dimensional spatial structure, providing sufficient space for bone cell growth, extension, and proliferation.

[0004] Currently, electrospinning technology is mainly divided into layer-by-layer spinning and hot pressing. However, the hot pressing method is difficult to control precisely and has a complex preparation method. During the preparation process, the bone tissue regeneration guiding membrane is prone to melting and deformation, making it difficult to guarantee its pore structure. The bone tissue regeneration guiding membrane prepared by layer-by-layer spinning has a high porosity and large pore size, which cannot play a sufficient physical shielding role. Fibroblasts can easily enter the fibrous membrane, causing the fibrous membrane to thicken and resulting in membrane exposure. Membrane exposure is one of the most common postoperative complications, which may cause contamination of bone replacement materials or even local tissue infection, leading to surgical failure.

[0005] Furthermore, existing oral repair membrane materials typically incorporate natural hydrophilic materials such as collagen, gelatin, and polysaccharides with synthetic materials like polylactic acid to form a composite membrane. This promotes adhesion and growth between tissue cells and the membrane, improving the biocompatibility and tissue repair performance of the oral repair membrane. However, in situations where there is a high amount of tissue fluid or other fluids present for an extended period (such as saliva), the hydrophilic materials in the repair membrane, such as collagen, gelatin, and polysaccharides, can swell. This can lead to structural changes such as fiber slippage or membrane deformation. These changes often result in poor adhesion of the membrane at the implantation site, post-implantation displacement, or loss of its original pore shielding function, leading to exposure and infection problems. Fixation with bone screws is usually necessary, which is cumbersome, and bone screws are typically non-absorbable, affecting aesthetics.

[0006] Reference 1 discloses a tissue regeneration guiding membrane, comprising a smooth layer, an intermediate layer, and a rough layer. The smooth layer is prepared by electrospinning poly(L-lactide-co-caprolactone). The intermediate layer is prepared by electrospinning poly(L-lactide-co-caprolactone) and type I collagen. The rough layer is prepared by electrospinning type I collagen and mineralized collagen together by electrospraying. However, this method cannot improve the adhesion of oral membranes.

[0007] Reference 2 discloses an oral repair membrane and its preparation method. When the biodegradable polymer material used to prepare the shielding layer and tissue scaffold layer of the oral repair membrane is polyhydroxyalkanoate, the prepared oral repair membrane has both good mechanical properties and degradation properties. The polyhydroxyalkanoate is a blend of poly(3-hydroxybutyric acid) and poly(4-hydroxybutyric acid) copolymer or poly(3-hydroxybutyric acid) and poly(3-hydroxyhexanoic acid) copolymer, but it still cannot improve the adhesion of the oral membrane.

[0008] References:

[0009] Reference 1: CN114129778A

[0010] Reference 2: CN112999430A Summary of the Invention

[0011] The problem the invention aims to solve

[0012] In view of the technical problems existing in the prior art, such as the difficulty in preparing oral repair membranes with suitable pore size and good shielding effect using conventional raw materials, and the problems of poor adhesion and easy slippage and deformation of existing oral repair membranes, the present invention first provides an oral repair membrane. The oral repair membrane of the present invention can better shield fibroblasts from growing into the fibrous membrane, avoiding the problem of membrane thickening caused by fibroblast growth, and has good softness and adhesion, preventing slippage during use, avoiding the risk of membrane exposure, and reducing the exposure infection rate.

[0013] Furthermore, the present invention also provides a method for preparing an oral repair membrane, which is simple and easy to implement, uses readily available raw materials, and is suitable for mass production.

[0014] Solution for solving the problem

[0015] This invention provides an oral repair membrane, comprising:

[0016] The matrix, wherein the matrix is ​​composed of interlocking and entwined fibers with a diameter of 10 nm-100 μm, and has a porous structure; and

[0017] Active particles, wherein the active particles are loaded on the surface and / or inside the matrix, and the active particles are derived from piezoelectric materials and / or hydrophilic polymer materials;

[0018] Preferably, based on the total mass of the oral repair membrane as 100%, the content of active particles in the oral repair membrane is 3%-40%, more preferably, the content of active particles in the oral repair membrane is 5%-35%.

[0019] Further, the average pore size of the oral repair membrane is 0.1-5 μm, preferably 0.5-3 μm; and / or

[0020] The softness of the oral repair membrane is below 1000mN, preferably below 700mN.

[0021] Further, the material of the matrix is ​​derived from piezoelectric material and / or elastomer material; preferably, the material of the matrix is ​​derived from piezoelectric material and elastomer material; more preferably, the mass ratio of piezoelectric material to elastomer material is (2-8):1; most preferably, the mass ratio of piezoelectric material to elastomer material is (3-6):1.

[0022] Furthermore, the elastomer material includes one or more of polytrimethylene carbonate, polyurethane elastomer, polyethylene elastomer, and polyurea elastomer.

[0023] Furthermore, the active particles are derived from piezoelectric materials and hydrophilic polymer materials. Preferably, the mass of the hydrophilic polymer material is less than 1 / 2 of the mass of the piezoelectric material.

[0024] Furthermore, the piezoelectric material comprises one or more combinations of polyhydroxyalkanoates;

[0025] Preferably, the polyhydroxy fatty acid ester includes one or more combinations of copolymers of 3-hydroxybutyrate and 3-hydroxyvalerate, poly-β-hydroxybutyrate, poly-3-hydroxybutyrate, and copolymers of 3-hydroxybutyrate and 4-hydroxybutyrate.

[0026] Furthermore, the hydrophilic polymer material includes one or more of gelatin, polyethylene glycol, polyvinyl alcohol, polystyrene, and polyurethane.

[0027] The present invention also provides a method for preparing the oral repair membrane according to the above, which includes the step of compounding a matrix and active particles.

[0028] Furthermore, the preparation method includes the following steps:

[0029] The piezoelectric material and / or elastomer material are dissolved in a solvent to obtain a matrix solution;

[0030] An active solution is obtained by dissolving piezoelectric materials and / or hydrophilic polymers in a solvent;

[0031] While spinning the matrix solution to form a matrix, the active solution is sprayed onto the matrix, so that the matrix and active particles are compositely formed to obtain a preform.

[0032] The preform is washed and dried to obtain an oral repair membrane.

[0033] Further, in the matrix solution, the mass-to-volume ratio of the spinning raw material to the solvent is (8-14) g / 100 ml; and / or,

[0034] In the active solution, the mass-to-volume ratio of the piezoelectric material and / or hydrophilic polymer to the solvent is (1-6) g / 100 ml.

[0035] The effects of the invention

[0036] The oral repair membrane of this invention has a porous structure with a suitable pore size, which can better shield fibroblasts from growing into the fibrous membrane and avoid the problem of membrane thickening caused by fibroblast growth. It can also block fast-migrating fibroblasts and surrounding tissues such as epithelial cells from entering the bone defect area, thus providing a good physical shielding effect. The oral repair membrane is soft in texture, has good adhesion, is easy to use, does not require bone screws for fixation, and will not slip during use, reducing the exposure infection rate.

[0037] The method for preparing the oral repair membrane of the present invention is simple and easy to implement, the raw materials are readily available, and it is suitable for mass production. Attached Figure Description

[0038] Figure 1A scanning electron microscope image (magnification ×200) of the oral repair membrane of Example 1 is shown;

[0039] Figure 2 A scanning electron microscope image (magnification × 1000) of the oral repair membrane of Example 1 is shown;

[0040] Figure 3 A scanning electron microscope image (magnification ×200) of the oral repair membrane of Comparative Example 1 is shown;

[0041] Figure 4 A scanning electron microscope image (magnification × 10000) of the oral repair membrane of Comparative Example 1 is shown;

[0042] Figure 5 A scanning electron microscope image (magnification ×200) of the oral repair membrane of Comparative Example 2 is shown;

[0043] Figure 6 A scanning electron microscope image (magnification × 10000) of the oral repair membrane of Comparative Example 2 is shown;

[0044] Figure 7 The adhesion of the oral repair membrane of Example 1 to the alveolar bone of a dog is shown;

[0045] Figure 8 The adhesion of the oral repair membrane of Comparative Example 1 to the alveolar bone of a dog is shown;

[0046] Figure 9 This diagram illustrates subcutaneous implantation in an animal experiment—a subcutaneous implantation experiment.

[0047] Figure 10 Comparative diagrams show the use of oral repair membranes from Example 1, Comparative Example 1, and Comparative Example 2 for subcutaneous implantation in rabbits.

[0048] Figure 11 The following are pathological observations of tissue cell penetration at the implantation site after dissection at 5 and 20 days, respectively, using an animal model with an oral repair membrane from Example 1 for subcutaneous implantation.

[0049] Figure 12 The following are pathological observations of tissue cell penetration at the implantation site after dissection at 5 and 20 days, respectively, using the oral repair membrane of Comparative Example 1 for subcutaneous implantation in an animal model.

[0050] Figure 13 The following are pathological observations of tissue cell penetration at the implantation site after dissection at 5 and 20 days, respectively, using the oral repair membrane of Comparative Example 2 for subcutaneous implantation in an animal model. Detailed Implementation

[0051] Various exemplary embodiments, features, and aspects of the present invention will be described in detail below. The term "exemplary" as used herein means "serving as an example, embodiment, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior to or better than other embodiments.

[0052] Furthermore, to better illustrate the present invention, numerous specific details are set forth in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. In other instances, methods, means, apparatus, and steps well known to those skilled in the art have not been described in detail in order to highlight the spirit of the present invention.

[0053] Unless otherwise stated, all units used in this specification are international standard units, and all numerical values ​​and ranges appearing in this invention should be understood to include systematic errors that are unavoidable in industrial production.

[0054] In this specification, the word "may" has two meanings: to perform a certain process and not to perform a certain process.

[0055] In this specification, references to "some specific / preferred embodiments," "other specific / preferred embodiments," "implementation," etc., refer to specific elements (e.g., features, structures, properties, and / or characteristics) related to that embodiment, which are included in at least one of the embodiments described herein and may or may not be present in other embodiments. Furthermore, it should be understood that these elements may be combined in any suitable manner in various embodiments.

[0056] In this specification, the range of values ​​referred to as “value A - value B” is the range that includes the endpoint values ​​A and B.

[0057] In this instruction manual, when "room temperature" or "room temperature" is used, the temperature can be 10-25℃.

[0058] <First Aspect>

[0059] A first aspect of the present invention provides an oral repair membrane, comprising:

[0060] The matrix, wherein the matrix is ​​composed of interwoven fibers with a diameter of 10 nm-100 μm and has a porous structure; and

[0061] Active particles, which are loaded on the surface and / or inside the matrix, and are derived from piezoelectric materials and / or hydrophilic polymers.

[0062] In some specific embodiments, the average pore size of the oral repair membrane is 0.1-5 μm, preferably 0.5-3 μm; and / or, the softness of the oral repair membrane is below 1000 mN, preferably below 700 mN. When the average pore size of the oral repair membrane is 0.1-5 μm (preferably 0.5-3 μm), it can better shield the membrane thickening caused by fibroblast ingrowth into the fibrous membrane, and prevent rapidly migrating fibroblasts and surrounding tissues such as epithelial cells from entering the bone defect area, thus providing a good physical shielding effect. When the softness of the oral repair membrane is below 1000 mN (preferably below 700 mN), the oral repair membrane is soft in texture, has good adhesion, is easy to use, and will not cause displacement or exposure infection problems after implantation.

[0063] matrix

[0064] The matrix of this invention is composed of interwoven fibers with a diameter of 10 nm to 100 μm and has a porous structure. The fibers can be obtained by spinning the matrix material through a spinning process.

[0065] In this invention, the matrix material is derived from piezoelectric materials and / or elastomer materials. Cell membranes possess electrical potentials, including resting potentials and action potentials. The resting potential is the potential difference across the membrane of a tissue cell in a resting state. The action potential is the potential change that occurs when a cell is stimulated, based on the resting potential. In this invention, the piezoelectric material can be hydrophobic, preventing swelling in environments with abundant or prolonged amounts of tissue fluid or other fluids (such as saliva). Furthermore, the piezoelectric coefficient of the material is closer to that of human cells and natural components, thus promoting cell growth. The oral repair membrane of this invention utilizes the attraction between the potential of the piezoelectric material and the cell's potential to generate better adhesion, reducing the exposure infection rate.

[0066] Preferably, the matrix material is derived from piezoelectric and elastomer materials. Using a blend of piezoelectric and elastomer materials allows for smaller pore sizes in the electrospun fiber membrane, better shielding against fibroblast ingrowth into the membrane, preventing membrane thickening, and reducing the exposure infection rate.

[0067] In some specific implementations, the mass ratio of the piezoelectric material to the elastomer material is (2-8):1, preferably (3-6):1, for example: 2.5:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, etc.; this results in a fiber membrane with smaller pore size obtained by blending the piezoelectric material and the elastomer material, which can better shield fibroblasts from growing into the fiber membrane.

[0068] Specifically, in this invention, the piezoelectric material comprises one or more combinations of polyhydroxy fatty acid esters; preferably, the polyhydroxy fatty acid ester comprises one or more combinations of a copolymer of 3-hydroxybutyrate and 3-hydroxyvalerate (PHBV), poly-β-hydroxybutyrate (PHB), poly-3-hydroxybutyrate (P3HB), and a copolymer of 3-hydroxybutyrate and 4-hydroxybutyrate (P34HB).

[0069] Furthermore, the elastomer material includes one or more of polytrimethylene carbonate, polyurethane elastomer, polyethylene elastomer, and polyurea elastomer. Preferably, the elastomer material is polytrimethylene carbonate, which has good biocompatibility and degradation properties, a short degradation cycle in the oral environment, and degrades to an alkaline state, greatly reducing the possibility of inflammation during the degradation process.

[0070] active granules

[0071] The active particles of this invention are loaded on the surface and / or interior of the substrate, and the active particles are derived from piezoelectric materials and / or hydrophilic polymers. This invention effectively solves the problem of slippage and deformation of oral repair membranes by loading active particles on the surface and / or interior of the substrate. Furthermore, by using piezoelectric materials and / or hydrophilic polymers as active particles, this invention improves the softness of the fibrous membrane, giving it better adhesion.

[0072] In some specific implementations, based on the total mass of the oral repair membrane as 100%, the content of active particles in the oral repair membrane is 3%-40%, preferably 5%-35%, for example: 8%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, 30%, 32%, 35%, 38%, etc. In this case, the oral repair membrane has good adhesion and good mechanical properties.

[0073] Specifically, in this invention, the piezoelectric material may be the same as or different from the piezoelectric material in the matrix. The piezoelectric material comprises one or more combinations of polyhydroxyalkanoates; preferably, the polyhydroxyalkanoate comprises one or more combinations of copolymers of 3-hydroxybutyrate and 3-hydroxyvalerate (PHBV), poly-β-hydroxybutyrate (PHB), poly-3-hydroxybutyrate (P3HB), and copolymers of 3-hydroxybutyrate and 4-hydroxybutyrate (P34HB).

[0074] Furthermore, the hydrophilic polymer material includes one or more of gelatin, polyethylene glycol, polyvinyl alcohol, polystyrene, and polyurethane.

[0075] In some specific embodiments, the active particles are derived from piezoelectric materials and hydrophilic polymers. Using piezoelectric and hydrophilic polymers further improves the softness and adherence of the oral repair membrane. Preferably, the mass of the hydrophilic polymer is less than half the mass of the piezoelectric material. When the mass of the hydrophilic polymer is less than half the mass of the piezoelectric material, the oral repair membrane exhibits good softness and adherence, and does not swell or thicken, thus not affecting its physical shielding effect.

[0076] The piezoelectric material, elastomeric polymer material, and hydrophilic polymer material used in the oral repair membrane of the present invention all have good biodegradability and biocompatibility.

[0077] <Second aspect>

[0078] A second aspect of the present invention provides a method for preparing an oral repair membrane according to the first aspect of the present invention, comprising the step of compounding a matrix and active particles.

[0079] In some specific embodiments, the preparation method of the present invention includes the following steps:

[0080] The piezoelectric material and / or elastomer material are dissolved in a solvent to obtain a matrix solution;

[0081] An active solution is obtained by dissolving piezoelectric materials and / or hydrophilic polymers in a solvent;

[0082] While spinning the matrix solution to form a matrix, the active solution is sprayed onto the matrix, so that the matrix and active particles are compositely formed to obtain a preform.

[0083] In this invention, the spinning process includes one or more of the following: electrospinning technology, centrifugal spinning technology, hot melt spinning technology, and melt electrospinning technology, preferably electrospinning technology.

[0084] The principle of electrospinning is that a high voltage is applied to a polymer liquid during the electrospinning process, introducing charge into the liquid. When the charge in the liquid accumulates to a certain amount, the liquid forms a Taylor cone at the nozzle. Under the action of the applied electric field, it overcomes surface tension to form a liquid jet. Then, under the combined action of electrostatic repulsion, Coulomb force, and surface tension, the polymer jet moves along an irregular spiral trajectory. The jet is stretched and pulled in a very short time, and as the solvent evaporates or heat dissipates, the polymer jet solidifies to form micro / nanofibers. During the electrospinning process, many parameters affect the final electrospun fibers. By controlling the process parameters, micro / nanofibers of different sizes, morphologies, and structures can be prepared.

[0085] In the electrospinning process of this invention, the process parameters affect the nanofiber material obtained by electrospinning. By controlling the process parameters, matrices of different sizes, morphologies, and structures can be prepared. This invention does not have special requirements for the electrospinning method; any electrospinning method commonly used in the art can be used.

[0086] In this invention, the electrospinning process may include the following steps: preparing fiber raw materials in advance, dissolving the fiber raw materials in a suitable solvent to prepare a spinning solution of a certain concentration. The fiber raw materials may be piezoelectric materials and / or elastomer materials as described in the first embodiment. This invention utilizes piezoelectric materials and / or elastomer materials to obtain a matrix through electrospinning, resulting in a matrix with suitable pore size, good mechanical properties, and reduced breakage during spinning, facilitating filament formation.

[0087] Furthermore, while spinning the matrix solution to form the matrix using a spinning process, the active solution is sprayed onto the matrix, causing the matrix and active particles to be composited and formed into a preform. The spraying method can be electrostatic spraying, thereby enabling the matrix and active particles to be composited and formed.

[0088] Electrostatic spraying is a method that uses electrohydrodynamic jet technology to prepare polymer solutions or melts into micron or nanoparticles. The basic principle of electrostatic spraying is to apply a high voltage when the polymer solution or melt flows out of a solution storage device at a certain speed. This causes a large amount of charge to accumulate inside the polymer fluid. Under the action of charge repulsion, a jet of fine streams is generated. Under the influence of the applied electric field, the jet becomes unstable due to the stretching effect of the electric field force, and simultaneously generates irregular spiral motions with extremely high frequencies. The jet is rapidly thinned and solidified into micro / nanoparticles along with the rapid evaporation of the solvent. These particles then move to a receiving device and are deposited. The principle and process of electrostatic spraying are largely the same as those of electrospinning.

[0089] In this invention, the droplets formed by electrostatic spraying are smaller, resulting in finer and more uniform active particles that bind to the substrate, ultimately leading to a more flexible and adherent oral repair film.

[0090] Specifically, preferably, in the matrix solution, the mass-to-volume ratio of spinning raw material to solvent is (8-14) g / 100 ml, for example: 9 g / 100 ml, 10 g / 100 ml, 11 g / 100 ml, 12 g / 100 ml, 13 g / 100 ml, 14 g / 100 ml, etc.; the matrix prepared using spinning raw material of this concentration has good mechanical properties; in the active solution, the mass-to-volume ratio of piezoelectric material and / or hydrophilic polymer material to solvent is (1-6) g / 100 ml, for example: 2 g / 100 ml, 3 g / 100 ml, 4 g / 100 ml, 5 g / 100 ml, etc.; using an active solution of this concentration for electrostatic spraying allows the active solution to be uniformly atomized, resulting in more suitable and uniform particle size of the formed active particles, which can be evenly distributed on the surface and / or inside the matrix.

[0091] There are no particular restrictions on the specific concentration of the solvent used to form the matrix solution and / or active solution, as long as it meets the requirements of the subsequent electrospinning process. For example, suitable solvents can be one or a combination of two or more of hexafluoroisopropanol, trifluoroethanol, chloroform, dichloromethane, and N,N'-dimethylformamide.

[0092] Specifically, in this invention, the conditions for electrospinning and electrospraying can be the same or different. Specifically, during electrospinning, the rate of the micro-injection pump is adjusted to 3-15 mL / h, the voltage of the high-voltage generator is adjusted to 10-26 kV, and the receiving distance of the receiving device is adjusted to 18-24 cm. During electrospraying, the rate of the micro-injection pump is adjusted to 3-15 mL / h, the voltage of the high-voltage generator is adjusted to 10-26 kV, and the receiving distance of the receiving device is adjusted to 18-24 cm.

[0093] In some specific embodiments, the preparation method of the present invention further includes eluting and drying the preform to obtain an oral repair membrane. The purpose of elution in the present invention is to remove the solvent. Specifically, the elution step may include eluting the preform with an eluent to remove the solvent. The eluent comprises a mixture of alcohol and water, preferably a mixture of ethanol and water, more preferably, the mass fraction of ethanol in the mixture of ethanol and water is 75%-95%, for example: 75%, 80%, 85%, 90%, 95%, etc. Specifically, in the present invention, the mixture of ethanol and water can be used for repeated soaking and elution to remove the solvent as completely as possible. After elution, drying is performed to further remove these solutions containing alcohols. Such drying can be carried out under heating and / or reduced pressure.

[0094] Example

[0095] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0096] Example 1

[0097] (1) Mix poly-β-hydroxybutyric acid (PHB) and polytrimethylene carbonate (PTMC) at a mass ratio of 5:1, then add hexafluoroisopropanol to prepare a solution with a mass-volume ratio of 12g / 100mL, and stir until homogeneous to form solution A.

[0098] (2) Dissolve poly-β-hydroxybutyric acid (PHB) in hexafluoroisopropanol solvent at a mass-volume ratio of 5g / 100mL and stir until homogeneous to form solution B.

[0099] (3) Load solution A into a syringe and solution B into another syringe. Adjust the rate of the micro-injection pump to 12 mL / h, adjust the voltage difference of the high voltage generator to 24 KV, and adjust the receiving distance of the receiving device to 20 cm. While electrospinning solution A to form a matrix, spray solution B onto the matrix using electrostatic spraying to obtain a preform.

[0100] (4) The preform from (3) was repeatedly soaked in 95% ethanol solution to remove hexafluoroisopropanol residue, and then dried to obtain an oral repair membrane, wherein the content of active particles was approximately 29.4%; its scanning electron microscope image is shown below. Figure 1 and Figure 2 shown.

[0101] Example 2

[0102] (1) Mix poly-β-hydroxybutyric acid (PHB) and polyurethane (TPU) at a mass ratio of 6:1, then add a mixed solvent of N,N-dimethylformamide (DMF) and chloroform at a mass-volume ratio of 3:1 to prepare a solution A with a mass-volume ratio of 10g / 100mL. Stir well to form solution A.

[0103] (2) Dissolve poly-β-hydroxybutyric acid (PHB) in hexafluoroisopropanol solvent at a mass-volume ratio of 5g / 100mL and stir until homogeneous to form solution B.

[0104] (3) Load solution A into a syringe and solution B into another syringe. Adjust the rate of the micro-injection pump to 4 mL / h, adjust the voltage difference of the high voltage generator to 24 KV, and adjust the receiving distance of the receiving device to 20 cm. While electrospinning solution A to form a matrix, spray solution B onto the matrix using electrostatic spraying to obtain a preform.

[0105] (4) The preform in (3) is repeatedly soaked in 95% ethanol solution to remove N,N-dimethylformamide (DMF) and residual chloroform and hexafluoroisopropanol, and then dried to obtain an oral repair membrane, wherein the content of active particles is about 33.3%.

[0106] Example 3

[0107] (1) The copolymer of 3-hydroxybutyrate and 3-hydroxyvalerate (PHBV) and polytrimethylene carbonate (PTMC) are mixed evenly at a mass ratio of 3:1, and then added to trifluoroethanol to prepare a solution A with a mass-volume ratio of 8g / 100mL.

[0108] (2) Dissolve the copolymer of 3-hydroxybutyrate and 3-hydroxyvalerate (PHBV) in hexafluoroisopropanol solvent at a mass-volume ratio of 3 g / 100 mL and stir until homogeneous to form solution B.

[0109] (3) Load solution A into a syringe and solution B into another syringe. Adjust the rate of the micro-injection pump to 8 mL / h, adjust the voltage difference of the high voltage generator to 10 KV, and adjust the receiving distance of the receiving device to 18 cm. While electrospinning solution A to form a matrix, electrostatic spraying is used to spray solution B onto the matrix to obtain a preform.

[0110] (4) The preform in (3) is repeatedly soaked in 95% ethanol solution to remove the residues of trifluoroethanol and hexafluoroisopropanol, and then dried to obtain an oral repair membrane, wherein the content of active particles is about 27.3%.

[0111] Example 4

[0112] (1) Mix poly-β-hydroxybutyric acid (PHB) and polytrimethylene carbonate (PTMC) at a mass ratio of 8:1, then add them to hexafluoroisopropanol solvent to prepare a solution with a mass-volume ratio of 12g / 100mL, and stir evenly to form solution A.

[0113] (2) Dissolve gelatin in hexafluoroisopropanol solvent at a mass-volume ratio of 1g / 100mL and stir until homogeneous to form solution B.

[0114] (3) Load solution A into a syringe and solution B into another syringe. Adjust the rate of the micro-injection pump to 3 mL / h, adjust the voltage difference of the high voltage generator to 24 KV, and adjust the receiving distance of the receiving device to 24 cm. While electrospinning solution A to form a matrix, spray solution B onto the matrix using electrostatic spraying to obtain a preform.

[0115] (4) The preform in (3) is repeatedly soaked in 95% ethanol solution to remove hexafluoroisopropanol residue, and then dried to obtain an oral repair membrane, wherein the content of active particles is about 7.7%.

[0116] Example 5

[0117] (1) Mix poly-β-hydroxybutyric acid (PHB) and polytrimethylene carbonate (PTMC) at a mass ratio of 2:1, then add them to hexafluoroisopropanol solvent to prepare a solution with a mass-volume ratio of 12g / 100mL, and stir evenly to form solution A.

[0118] (2) Dissolve gelatin in hexafluoroisopropanol solvent at a mass-volume ratio of 2g / 100mL and stir until homogeneous to form solution B.

[0119] (3) Dissolve poly-β-hydroxybutyric acid (PHB) in hexafluoroisopropanol solvent at a mass-volume ratio of 4 g / 100 mL and stir until homogeneous to form solution C.

[0120] (4) Load solution A into a syringe, solution B into another syringe, and solution C into another syringe. Adjust the rate of the micro-injection pump to 4 mL / h, adjust the voltage difference of the high voltage generator to 24 KV, and adjust the receiving distance of the receiving device to 20 cm. While electrospinning solution A to form a matrix, electrostatic spraying is used to spray solution B and solution C onto the matrix to obtain a preform.

[0121] (5) The preform in (4) is repeatedly soaked in 95% ethanol solution to remove hexafluoroisopropanol residue, and then dried to obtain an oral repair membrane, wherein the content of active particles is about 33.3%.

[0122] Example 6

[0123] (1) Dissolve poly-β-hydroxybutyric acid (PHB) in hexafluoroisopropanol solvent at a mass-volume ratio of 12g / 100mL and stir until homogeneous to form solution A.

[0124] (2) Dissolve poly-β-hydroxybutyric acid (PHB) in hexafluoroisopropanol solvent at a mass-volume ratio of 5g / 100mL and stir until homogeneous to form solution B.

[0125] (3) Load solution A into a syringe and solution B into another syringe. Adjust the rate of the micro-injection pump to 12 mL / h, adjust the voltage difference of the high voltage generator to 24 KV, and adjust the receiving distance of the receiving device to 20 cm. While electrospinning solution A to form a matrix, spray solution B onto the matrix using electrostatic spraying to obtain a preform.

[0126] (4) The preform in (3) is repeatedly soaked in 95% ethanol solution to remove hexafluoroisopropanol residue, and then dried to obtain an oral repair membrane, wherein the content of active particles is about 29.4%.

[0127] Example 7

[0128] (1) Dissolve polytrimethylene carbonate (PTMC) in hexafluoroisopropanol solvent at a mass-volume ratio of 8g / 100mL and stir until homogeneous to form solution A.

[0129] (2) Dissolve gelatin in hexafluoroisopropanol solvent at a mass-volume ratio of 1g / 100mL and stir until homogeneous to form solution B.

[0130] (3) Load solution A into a syringe and solution B into another syringe. Adjust the rate of the micro-injection pump to 3 mL / h, adjust the voltage difference of the high voltage generator to 24 KV, and adjust the receiving distance of the receiving device to 24 cm. While electrospinning solution A to form a matrix, spray solution B onto the matrix using electrostatic spraying to obtain a preform.

[0131] (4) The preform in (3) is repeatedly soaked in 95% ethanol solution to remove hexafluoroisopropanol residue, and then dried to obtain an oral repair membrane, wherein the content of active particles is about 11.1%.

[0132] Comparative Example 1

[0133] (1) Mix poly-β-hydroxybutyric acid (PHB) and polytrimethylene carbonate (PTMC) at a mass ratio of 5:1, then add hexafluoroisopropanol to prepare a mass-volume ratio of 12g / 100mL, stir evenly to obtain PHB / PTMC spinning solution.

[0134] (2) Load the PHB / PTMC spinning solution into a syringe, adjust the rate of the micro-injection pump to 12 mL / h, adjust the voltage difference of the high voltage generator to 24 KV, adjust the receiving distance of the receiving device to 20 cm, and perform electrospinning to obtain a preform.

[0135] (3) The preform from (2) was repeatedly immersed in 95% ethanol solution to remove hexafluoroisopropanol residue, and then dried to obtain an oral repair membrane. Its scanning electron microscope image is shown below. Figure 3 and Figure 4 shown.

[0136] Comparative Example 2

[0137] (1) Poly-β-hydroxybutyric acid (PHB) was dissolved in hexafluoroisopropanol solvent at a mass-volume ratio of 12g / 100mL and stirred evenly to obtain PHB spinning solution.

[0138] (2) Load the PHB spinning solution into a syringe, adjust the rate of the micro-injection pump to 12 mL / h, adjust the voltage difference of the high voltage generator to 24 KV, adjust the receiving distance of the receiving device to 20 cm, and perform electrospinning to obtain a preform.

[0139] (3) The preform from (2) was repeatedly immersed in 95% ethanol solution to remove hexafluoroisopropanol residue, and then dried to obtain an oral repair membrane. Its scanning electron microscope image is shown below. Figure 5 and Figure 6 shown.

[0140] Performance testing

[0141] 1. Pore size of oral repair membrane

[0142] The average pore size of the oral repair membranes of Examples 1-7 and the comparative examples was measured by mercury intrusion porosimetry, and the results are shown in Table 1 below.

[0143] Table 1

[0144] Sample number Average aperture Example 1 0.8 Example 2 1.0 Example 3 0.7 Example 4 1.3 Example 5 1.5 Example 6 4.8 Example 7 1.7 Comparative Example 1 1.1 Comparative Example 2 5.3

[0145] As can be seen from Table 1, the average pore size of the oral repair membranes of Examples 1-7 of this application is significantly lower than that of the oral repair membrane of Comparative Example 2. The results of Comparative Examples 1 and 2 demonstrate that blending the piezoelectric material PHB with the elastomeric polymer material PTMC can result in a smaller pore size in the electrospun fiber membrane.

[0146] 2. Softness test of oral repair membrane

[0147] The softness was determined according to the method of GB / T 8942-2002; the softness value is the sum of the maximum vector of the bending resistance of the oral repair membrane and the friction between the oral repair membrane and the gap, expressed in millinewtons (mN). The smaller the softness value, the softer the oral repair membrane and the better its adhesion. The results are shown in Table 2 below.

[0148] Table 2

[0149]

[0150] As can be seen from Table 2, the oral repair membrane of the present invention is softer and has superior operability compared to the oral repair membrane of Comparative Example 1. Therefore, the oral repair membrane of the present invention, comprising a matrix and active particles loaded on the surface and / or interior of the matrix, has superior softness and is more suitable for oral repair than Comparative Example 1.

[0151] 3. Adhesion test of oral repair film

[0152] The oral repair films of Example 1 and Comparative Example 1 were respectively soaked in water and blood. After being fully moistened, they were directly applied to the alveolar bone of dogs, and the adhesion of the films was observed. The results are as follows: Figure 7 and Figure 8 As shown.

[0153] Depend on Figure 7 It can be seen that the oral repair membrane of Example 1, after being soaked in water or blood, adheres well to the alveolar bone of dogs without the need for fixation; Figure 8 It can be seen that the oral repair membrane of Comparative Example 1, after being soaked in water or blood, adhered poorly to the alveolar bone of dogs compared to Example 1. This indicates that the oral repair membrane formed by the composite of the matrix and active particles can significantly improve its adhesion.

[0154] 4. Animal Experiments - Subcutaneous Implantation Experiment (Subcutaneous implantation into rabbit skin to observe membrane thickening and shielding effect)

[0155] The oral repair membrane samples prepared in Example 1, Comparative Example 1, and Comparative Example 2 were sterilized by irradiation and then used for subcutaneous implantation in animal models for evaluation.

[0156] After 7 days of acclimatization, New Zealand rabbits were induced with an intramuscular injection of 0.5 ml / kg of a hypnotherapy drug, followed by deep anesthesia via intravenous injection of 0.7 ml / kg of 3% sodium pentobarbital from the ear. After anesthesia, the rabbits were shaved from the back, fixed to the operating table, and disinfected with povidone-iodine solution. Oral repair membranes from Examples 1, 6, and the comparative examples were applied without further fixation. A skin incision approximately 1 cm long was made at each implantation site on both sides of the spine, spaced approximately 2 cm apart and 2 cm from the spine. Subcutaneous tissue was bluntly dissected down to the superficial fascia and muscle layer. Five subcutaneous bursae were created on each side of each animal. A schematic diagram of the subcutaneous implantation is shown below. Figure 9 As shown. Close the incision and suture the subcutaneous tissue and skin in layers. Disinfect the wound with povidone-iodine. See the diagram for the subcutaneous implant. Figure 9 As shown.

[0157] After the surgery, the animals were placed back in their individual cages. For the first 5 days post-surgery, they were given intramuscular injections of injectable sodium penicillin and injectable streptomycin to combat infection. The animals were anatomically dissected on days 5 and 20, and the condition of the fibrous membrane was photographed. The fibrous membrane was then removed, placed in a fixative, and sent for pathological sectioning.

[0158] Figure 10 Comparative images show the oral repair membranes used in Example 1, Comparative Example 1, and Comparative Example 2 for subcutaneous implantation in rabbits. Figure 10 It can be seen that the oral repair membranes of Example 1 and Comparative Example 1 did not thicken after 20 days of implantation in rabbit skin; however, the oral repair membrane of Comparative Example 2 showed significant thickening of the fibrous membrane after 20 days of implantation in rabbit skin. This indicates that adding elastomer polymer materials during the electrospinning of piezoelectric materials can better shield fibroblasts from ingrowth into the fibrous membrane, avoiding membrane thickening caused by fibroblast ingrowth.

[0159] Figure 11 The images show pathological observations of tissue cell penetration at the implantation site in an animal model using the oral repair membrane of Example 1 for subcutaneous implantation, at 5 and 20 days post-dissection. Figure 11 It can be seen that on day 5, no obvious cell ingrowth into the membrane material was observed, and no other inflammatory cells were observed, indicating a very good shielding effect. On day 20, a small number of cells edrow into the membrane material at the edge, and a large number of macrophages and multinucleated giant cells engulfed the material (the membrane material began to degrade), and new blood vessels were observed to form locally (the membrane material has good biocompatibility), indicating a very good shielding effect.

[0160] Figure 12 The images show pathological observations of tissue cell penetration at the implantation site in an animal model using the oral repair membrane from Comparative Example 1 for subcutaneous implantation, at 5 and 20 days post-dissection. Figure 12 It can be seen that on day 5, no obvious cell ingrowth into the membrane material was observed, and no other inflammatory cells were observed, indicating a very good shielding effect. On day 20, a small number of cells edrow into the membrane material at the edge, and a large number of macrophages and multinucleated giant cells engulfed the material (the membrane material began to degrade), and new blood vessels were observed to form locally (the membrane material has good biocompatibility), indicating a very good shielding effect.

[0161] Figure 13 The image shows pathological observations of tissue cell penetration at the implantation site after dissection at 5 and 20 days, using an oral repair membrane prepared in Comparative Example 2 for subcutaneous implantation in an animal model. Figure 11 It can be seen that no significant fibroblast ingrowth into the membrane material was observed on day 5, and no other inflammatory cells were observed, indicating a certain shielding effect. On day 20, a large amount of tissue edged in from the muscle side, causing membrane material hyperplasia and thickening, and the shielding effect significantly deteriorated.

[0162] The above pathological results indicate that the oral repair membrane of this application has a good physical shielding effect; the matrix is ​​made of a blend of piezoelectric and elastomer materials, which can better shield fibroblasts from growing into the fiber membrane.

[0163] It should be noted that although the technical solution of the present invention has been described with specific examples, those skilled in the art will understand that the present invention should not be limited thereto.

[0164] The various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical application, or technical improvements to the embodiments in the market, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. An oral repair film, characterized in that, include: The matrix, comprising interlocking and entwining fibers with a diameter of 10 nm-100 μm and possessing a porous structure, is derived from piezoelectric materials and / or elastomer materials; and Active particles, wherein the active particles are loaded on the surface and / or inside the matrix, and the active particles are derived from piezoelectric materials and / or hydrophilic polymer materials; The piezoelectric material includes one or more combinations of polyhydroxyalkanoates; The average pore size of the oral repair membrane is 0.1-5 μm; The softness of the oral repair membrane is below 1000mN.

2. The oral repair film according to claim 1, wherein, Based on the total mass of the oral repair membrane as 100%, the content of active particles in the oral repair membrane is 3%-40%.

3. The oral repair film according to claim 2, wherein, The content of active particles in the oral repair membrane is 5%-35%.

4. The oral repair membrane according to any one of claims 1-3, characterized in that, The average pore size of the oral repair membrane is 0.5-3 μm; and / or The softness of the oral repair membrane is below 700mN.

5. The oral repair membrane according to any one of claims 1-3, characterized in that, The matrix material is derived from piezoelectric materials and elastomer materials.

6. The oral repair membrane according to claim 5, characterized in that, The mass ratio of the piezoelectric material to the elastomer material is (2-8):

1.

7. The oral repair membrane according to claim 6, characterized in that, The mass ratio of the piezoelectric material to the elastomer material is (3-6):

1.

8. The oral repair membrane according to any one of claims 1-3, characterized in that, The elastomer material includes one or more of the following: polytrimethylene carbonate, polyurethane elastomer, polyethylene elastomer, and polyurea elastomer.

9. The oral repair membrane according to any one of claims 1-3, characterized in that, The active particles are derived from piezoelectric materials and hydrophilic polymer materials.

10. The oral repair membrane according to claim 9, characterized in that, The mass of the hydrophilic polymer material is less than 1 / 2 of the mass of the piezoelectric material.

11. The oral repair membrane according to any one of claims 1-3, characterized in that, The polyhydroxy fatty acid esters include one or more combinations of copolymers of 3-hydroxybutyrate and 3-hydroxyvalerate, poly-β-hydroxybutyrate, poly-3-hydroxybutyrate, and copolymers of 3-hydroxybutyrate and 4-hydroxybutyrate.

12. The oral repair membrane according to any one of claims 1-3, characterized in that, The hydrophilic polymer material includes one or more of gelatin, polyethylene glycol, polyvinyl alcohol, and polyurethane.

13. A method for preparing an oral repair membrane according to any one of claims 1-12, characterized in that, This includes the step of combining the matrix and active particles.

14. The preparation method according to claim 13, characterized in that, Includes the following steps: The piezoelectric material and / or elastomer material are dissolved in a solvent to obtain a matrix solution; An active solution is obtained by dissolving piezoelectric materials and / or hydrophilic polymers in a solvent; While spinning the matrix solution to form a matrix, the active solution is sprayed onto the matrix, so that the matrix and active particles are compositely formed to obtain a preform. The preform is washed and dried to obtain an oral repair membrane.

15. The preparation method according to claim 14, characterized in that, In the matrix solution, the mass-to-volume ratio of spinning raw material to solvent is (8-14) g / 100 mL; and / or, In the active solution, the mass-to-volume ratio of the piezoelectric material and / or hydrophilic polymer to the solvent is (1-6) g / 100 mL.

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