Composite material for alveolar bone repair and preparation method thereof

Abstract

The present invention discloses a composite material for alveolar bone repair and a preparation method thereof; the composite material is composed of a dense layer having a soft tissue barrier function and a loose layer having a function of guiding bone tissue regeneration; wherein: the dense layer is a fiber membrane formed by stacking nanofibers, which is formed by electrostatic spinning of polyester medical polymer materials; the loose layer is a scaffold material for bone repair, which is formed by electrostatic spinning of a composite scaffold material; the composite scaffold material is bonded by nano-scale inorganic filling materials and polyester medical polymer materials. The composite material for alveolar bone repair provided by the present invention is formed by ultrasonic welding of a dense layer having a soft tissue barrier function and a loose layer guiding bone tissue regeneration; the present invention combines the soft tissue barrier membrane and bone filling material required for GBR technology into one, solving the problem that existing alveolar bone defect repair materials require the use of soft tissue barrier membranes and cannot provide independent bone formation space.

Description

Technical Field

[0001] The present invention relates to the technical field of nano-biomedicine, and in particular to a composite material for alveolar bone repair and a preparation method thereof. Background Art

[0002] After tooth extraction, the local alveolar ridge will undergo remodeling or absorption, resulting in a decrease in bone mass in the defect area, affecting denture restoration and implant placement. In severe cases, it can also cause atrophy of the surrounding soft tissue, affecting the quality of life.

[0003] Currently, the primary clinical treatment for this condition is guided bone regeneration (GBR) technology. It primarily combines a soft tissue barrier membrane with a bone filler material, utilizing the space created by the barrier membrane to allow osteoblasts or vascular endothelial cells to grow in while simultaneously isolating the overlying non-osteoblastic soft tissue cells from invading. This type of barrier membrane primarily consists of an absorbable collagen membrane, whose primary drawbacks are poor mechanical properties, rapid degradation, and an inability to maintain a stable bone formation space. The bone filler material utilizes its osteoconductive properties to provide a biological scaffold for the host's bone tissue, thereby promoting bone regeneration. This type of material is typically selected from autologous bone, allogeneic bone, and synthetic ceramic materials, and is provided in the form of granules or blocks. The disadvantages of this type of material are poor plasticity and easy dispersion, making it inconvenient for doctors to operate. Furthermore, the degradation rate does not match the rate of new bone formation, resulting in a prolonged foreign body reaction and considerable discomfort for patients. Existing bone filling materials have the following defects: (1) Existing bone filling materials cannot provide independent bone formation space and need to be used in conjunction with soft tissue barrier membranes, which results in high surgical costs and cumbersome operations; (2) The soft tissue barrier membranes required by existing bone filling materials have poor mechanical properties and degrade quickly, and cannot stably maintain the bone formation space; (3) Existing bone filling materials have poor plasticity and are easy to disperse, making them inconvenient to operate during use; (4) The degradation rate of existing bone filling materials does not match the rate of new bone formation, resulting in a long foreign body reaction time and poor ability to guide bone tissue regeneration.

[0004] Based on the shortcomings of existing bone filling materials, an ideal alveolar bone repair material should have the following characteristics: ① It has a specific tissue barrier function and certain mechanical properties, can form an independent and stable bone formation space, and provide a good scaffold environment for alveolar bone repair; ② It can be shaped at will without overflowing, which is convenient for clinicians to operate; ③ The degradation rate matches the bone formation rate, enhances the ability to guide bone tissue regeneration, and improves the patient experience. Summary of the Invention

[0005] The purpose of the present invention is to provide a composite material for alveolar bone repair and a preparation method thereof in response to the defects of existing bone filling materials. The composite material for alveolar bone repair of the present invention is mainly composed of a dense layer with a soft tissue barrier function and a loose layer that guides bone tissue regeneration. It meets the requirements of an ideal alveolar bone repair material, such as independent and stable bone formation space, arbitrary shaping, and appropriate degradation rate, thereby solving the pain points faced by existing bone filling materials.

[0006] The present invention is achieved through the following technical solutions:

[0007] A composite material for alveolar bone repair, characterized in that the composite material consists of a dense layer with a soft tissue barrier function and a loose layer with a bone tissue regeneration guidance function; wherein: the dense layer is a fiber membrane formed by stacking nanofibers, which is formed by electrostatic spinning of polyester medical polymer materials; the loose layer serves as a scaffold material for bone repair, which is formed by electrostatic spinning of a composite scaffold material; the composite scaffold material is formed by bonding nano-scale inorganic filler materials and polyester medical polymer materials.

[0008] Specifically, the inorganic nanofiller in the composite material of the present invention has a high specific surface area. Under physiological conditions, it interacts with the tissue interface, forming chemical bonds and providing nutrients such as calcium and phosphorus necessary for the growth of newly formed bone tissue. Furthermore, the polyester medical polymer, after processing through techniques such as electrospinning and 3D printing, forms a barrier system necessary for bone repair and perfectly fulfills its scaffolding function, providing a favorable physiological environment for the growth of newly formed bone. Therefore, the present invention combines the nanoscale inorganic filler and the polyester medical polymer through bonding to create a composite scaffold material with a suitable degradation rate.

[0009] In the composite material for alveolar bone repair provided by the present invention: the dense layer is a fiber membrane formed by stacking nanofibers, which is made of polyester medical polymer materials through electrospinning. Compared with the currently commonly used degradable biofilms, it has higher mechanical strength and controllable degradation rate, can provide a stable bone formation space for defective bone tissue, play a good shielding role, and prevent the invasion of soft tissue.

[0010] In the composite material for alveolar bone repair provided by the present invention: the loose layer serves as a scaffold layer for bone repair, which is made of a composite scaffold material processed by a specific electrospinning process; the loose layer obtained by the present invention has the characteristics of being able to be arbitrarily shaped, not overflowing, and having a controllable degradation rate.

[0011] Furthermore, a composite material for alveolar bone repair: the fiber diameter of the dense layer is 10-10000 nm, and the thickness of the dense layer is 0.1-0.5 cm.

[0012] Preferably, the diameter of the dense layer fibers is 50-5000 nm; preferably, the thickness of the dense layer is 0.25-0.5 cm.

[0013] Furthermore, a composite material for alveolar bone repair: the polyester medical polymer material is selected from one of poly(L-lactide-co-D,L-lactide), poly-L-lactide, poly(L-lactide-co-glycolide), poly(L-lactide-co-ε-caprolactone) and their modified products; the nanoscale inorganic filling material is selected from one of aminohydroxyapatite, silicate-doped calcium carbonate, β-tricalcium phosphate, bioactive glass, and biphasic calcium phosphate ceramics; the intrinsic viscosity of the polyester medical polymer material is 1.3-7.0dL / g.

[0014] A method for preparing a composite material for alveolar bone repair, characterized in that the method comprises the following steps:

[0015] 1. Preparation of dense layer:

[0016] S1, dissolving a polyester medical polymer material in a first solvent, then adding a second solvent, and stirring evenly to form a spinning solution A;

[0017] S2. Electrospinning the spinning solution A to obtain an electrospun membrane. Specifically, the electrospinning process in step S2 is as follows: loading the spinning solution A into a syringe with a needle aperture of 0.4 mm, an injection speed of 1.5-2.5 ml / h, a voltage of 15-30 kV, and a receiving distance of 8-22 cm to perform electrospinning to obtain an electrospun membrane.

[0018] S3, drying the electrospun membrane, and then stacking to obtain a dense layer;

[0019] 2. Preparation of loose layer:

[0020] S1. Drying the nanoscale inorganic filler material, then dissolving it in an organic solvent, and introducing HX gas to react to obtain a halogenated nanoscale inorganic filler material; wherein X is selected from one of Cl, Br, and I;

[0021] S2, dissolving the polyester medical polymer material in the organic solvent to obtain a solution; adding the solution dropwise to the halogenated nanoscale inorganic filler material, and then refluxing and stirring; after refluxing and stirring, removing the organic solvent, washing, and drying the resulting product to obtain a bonding product of the nanoscale inorganic filler material and the polyester medical polymer material, which is a composite stent material;

[0022] S3, dissolving the composite scaffold material, then adding a third solvent, and stirring evenly to obtain a spinning solution B;

[0023] S4, electrospinning the spinning solution B, and drying after spinning to obtain a cotton-like loose layer with good plasticity;

[0024] 3. Preparation of composite materials:

[0025] S1. Ultrasonic welding the loose layer to the dense layer to obtain a composite material for alveolar bone repair.

[0026] Furthermore, a method for preparing a composite material for alveolar bone repair: 1. Preparation of a dense layer: S1. Dissolve a polyester medical polymer material in a first solvent, and the concentration of the polyester medical polymer material is 16-20wt%, and then add a second solvent, stir evenly to form a spinning solution A; wherein: the first solvent is chloroform; the second solvent is selected from one of dimethylbenzamide, hexafluoroisopropanol, DMSO, trifluoroethanol, tetrahydrofuran, DMF, and toluene; the mass ratio of the first solvent to the second solvent is 1:(1-2).

[0027] Furthermore, a method for preparing a composite material for alveolar bone repair includes: 2. Preparation of a loose layer: Step S1: vacuum-drying a nanoscale inorganic filler material at 40-60°C for 24-48 hours, then dissolving the nanoscale inorganic filler material in an organic solvent, and slowly introducing HX gas at room temperature for a reaction of 1-3 hours to obtain a halogenated nanoscale inorganic filler material; wherein the organic solvent is chloroform, and the mass ratio of the nanoscale inorganic filler material to the organic solvent is 1:(2-5). Specifically, the vacuum degree in this step is below 200 bar.

[0028] Furthermore, a method for preparing a composite material for alveolar bone repair: 2. Preparation of a loose layer: Step S2, dissolving a polyester medical polymer material in chloroform to obtain a solution containing 10-20wt% of the polyester medical polymer material; then adding the solution dropwise to a halogenated nanoscale inorganic filler material and reflux stirring for 8-12 hours; after the reaction, rotary evaporation to remove the chloroform, rinsing the resulting product with purified water for 2-3 hours, and drying at 70-90°C for 2-4 hours to obtain a bonded product of the nanoscale inorganic filler material and the polyester medical polymer material; wherein: the molar ratio of the halogenated nanoscale inorganic filler material to the polyester medical polymer material is 1:(1-2).

[0029] Furthermore, a method for preparing a composite material for alveolar bone repair: 2. Preparation of a loose layer: Step S3, dissolving the obtained bonding product in chloroform, and the concentration of the bonding product is 18-26wt%, and then adding a third solvent and stirring evenly to obtain a spinning solution B; wherein: the mass ratio of the third solvent to the chloroform is 1: (1-2), and the third solvent is selected from one of dimethylbenzamide, hexafluoroisopropanol, DMSO, trifluoroethanol, tetrahydrofuran, DMF, and toluene.

[0030] Furthermore, a method for preparing a composite material for alveolar bone repair: 2. Preparation of a loose layer: Step S4, electrospinning the spinning solution B using a bell-mouth or centrifugal spinning method, and drying it at 80-120°C for 2-4 hours after spinning to obtain a cotton-like loose layer with good plasticity.

[0031] Furthermore, a method for preparing a composite material for alveolar bone repair is provided: 3. Preparation of composite material: S1. Spread the dense layer flat on the stainless steel interface, use an ultrasonic welding machine with a pressure of 0.1-0.3 MPa and a welding time of 0.1-0.3 s / point, and weld the loose layer on the dense layer at a distance of 0.1-0.3 mm per point to obtain a composite material for alveolar bone repair.

[0032] Beneficial effects of the present invention:

[0033] (1) The present invention provides a composite material for alveolar bone repair, which is formed by ultrasonic welding of a dense layer having a soft tissue barrier function and a loose layer for guiding bone tissue regeneration; the present invention combines the soft tissue barrier membrane and bone filling material required for guided bone regeneration (GBR) technology into one, solving the problem that existing alveolar bone defect repair materials require the use of soft tissue barrier membranes and cannot provide independent bone formation space.

[0034] (2) In the composite material for alveolar bone repair provided by the present invention, the dense layer having a soft tissue barrier function is obtained by electrospinning a polyester medical polymer material, and its degradation performance is controllable, and it can provide a stable bone formation space; the loose layer having the function of guiding bone tissue regeneration is obtained by bonding a nano-scale inorganic filler material and a polyester medical polymer, and then electrospinning the material. It has the advantages of being able to be shaped at will, having no bone powder spillage, having a stable structure and being easy to use and operate, and having suitable degradation performance, and can provide a good scaffold environment for regenerated bone tissue.

[0035] (3) The composite material for alveolar bone repair prepared by the present invention overcomes the disadvantage that existing bone filling materials must be used in combination with soft tissue barrier membranes, successfully achieves the dual functions of barrier and filling, and reduces surgical costs. The composite material prepared by the present invention solves the technical barrier that existing alveolar bone defect repair materials cannot shield soft tissue invasion and need to be used in combination with soft tissue barrier membranes.

[0036] (4) The degradation rate of the composite material for alveolar bone repair provided by the present invention matches the osteogenesis rate of new bone, which solves the problem that the degradation rate of existing bone filling materials does not match the osteogenesis rate of new bone, resulting in a long foreign body reaction time and poor ability to guide bone tissue regeneration. The composite material of the present invention has a strong ability to guide bone regeneration and a good patient experience.

[0037] (5) The composite material for alveolar bone repair provided by the present invention solves the defects of existing bone filling materials such as poor plasticity, easy dispersion, and inconvenience for doctors to operate and use; the composite material of the present invention also solves the problem that the soft tissue barrier membrane matched with the existing bone filling materials has poor mechanical properties, fast degradation rate, and cannot provide a stable bone formation space.

[0038] (6) The composite material for alveolar bone repair provided by the present invention is made of a dense layer and a loose layer through ultrasonic welding. The dense layer has high mechanical strength and controllable degradation rate, can provide a stable bone formation space for the defective bone tissue, play a good shielding role, and prevent the invasion of soft tissue; the loose layer has the characteristics of being able to be shaped at will (good plasticity), not overflowing, and having a controllable degradation rate; the present invention is based on the traditional alveolar bone repair technology that requires the use of bone filling materials and soft tissue barrier membranes, which is inconvenient to operate and has high use costs. Therefore, the composite scaffold material for alveolar bone repair of the present invention is made of a dense layer with a soft tissue barrier function and a loose layer that guides bone tissue regeneration through ultrasonic welding, which perfectly realizes the dual functions of shielding soft tissue and guiding bone tissue regeneration.

[0039] (7) The composite stent material prepared by the present invention is a material that bonds nano-scale inorganic filler material and organic polymer (polyester medical polymer material) material together through a nucleophilic reaction, which can avoid adverse reactions such as hemolysis and irritation caused by the nanomaterial.

[0040] (8) The composite material for alveolar bone repair described in the present invention is formed by bonding organic materials and inorganic materials, and then undergoing electrostatic spinning and ultrasonic welding. It has strong plasticity, is easy to use, and has a suitable degradation rate. It is a good double-layer biomaterial.

[0041] (9) Existing inorganic bone filling materials used for alveolar bone repair are generally particles with a particle size of 0.5-1.0 nm, so they have poor plasticity and are easy to disperse, which makes it inconvenient for doctors to operate and use. The composite material for alveolar bone repair provided by the present invention has an upper layer of a dense membrane layer that can be cut at will, and a lower layer is a loose layer obtained by electrospinning, which can be shaped at will according to the location of the defect. Therefore, the alveolar bone repair material provided by the present invention is more convenient for clinical use. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 Schematic diagram of injection to induce delayed-type hypersensitivity reaction. DETAILED DESCRIPTION

[0043] The following will be combined with the accompanying drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. The following description of at least one exemplary embodiment is actually only illustrative and is in no way intended to limit the present invention and its application or use. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0044] Example 1

[0045] A composite material for alveolar bone repair, characterized in that the composite material is ultrasonically welded from a dense layer serving as a soft tissue barrier and a loose layer serving as a guide for bone tissue regeneration; wherein: the dense layer is a fiber membrane formed by stacking nanofibers, formed by electrostatic spinning of a polyester medical polymer material; the loose layer serves as a scaffold material for bone repair, formed by electrostatic spinning of a composite scaffold material; the composite scaffold material is bonded by a nanoscale inorganic filler material (amino nanoscale hydroxyapatite, particle size: 100-300nm) and a polyester medical polymer material (poly-L-lactide, intrinsic viscosity: 1.5-2.0dL / g).

[0046] The method for preparing a composite material for alveolar bone repair described in the above embodiment 1 comprises the following specific steps:

[0047] 1. Preparation of dense layer:

[0048] S1. Dissolve a polyester medical polymer material (poly (L-lactide)) in chloroform to a concentration of 18 wt %. Then, add hexafluoroisopropanol (HFIP) in an amount equal to that of the chloroform and stir evenly to form a spinning solution A.

[0049] S2. The obtained spinning solution A is loaded into a syringe with a needle aperture of 0.4 mm, an injection speed of 1.5 ml / h, a voltage of 18 kV, and a receiving distance of 15 cm for electrospinning to obtain an electrospun membrane, which is a polyester medical polymer membrane; the electrospinning technology in this step adopts a needle spinning method, and the receiving interface is a flat receiving surface with a diameter of 5-10 cm;

[0050] S3, drying the obtained electrospun membrane at 80° C. for 4 hours, and then stacking the obtained electrospun membranes to obtain a dense layer;

[0051] 2. Preparation of loose layer:

[0052] S1. Dry the nanoscale inorganic filler material (amino nanoscale hydroxyapatite) in vacuum at 50° C. for 48 hours (the vacuum degree is below 200 bar), dissolve the dried material in chloroform (the mass ratio of the nanoscale inorganic filler material to chloroform is 1:3), and then slowly introduce HBr gas under stirring at room temperature for 3 hours to obtain a halogenated nanoscale inorganic filler material;

[0053] S2. Dissolving a certain amount of poly (L-lactide) in chloroform to obtain a chloroform solution containing 10 wt% poly (L-lactide), referred to as a dissolving solution; adding the dissolving solution dropwise to the halogenated nanoscale inorganic filler material obtained above (note: the molar ratio of amino nanoscale hydroxyapatite to poly (L-lactide) is 1:1), followed by reflux and stirring for 12 hours; after reflux and stirring, rotary evaporation is performed to remove the chloroform, and the bonded product is rinsed with purified water for 2 hours and dried at 80° C. for 4 hours to obtain a bonded product of the nanoscale inorganic filler material and the polyester medical polymer material, which is a composite stent material;

[0054] S3, dissolving the obtained composite scaffold material in chloroform and stirring evenly, wherein the concentration of the composite scaffold material is 20 wt %, and then adding hexafluoroisopropanol of the same mass as the chloroform and stirring evenly to obtain a spinning solution B;

[0055] S4, electrospinning the obtained spinning solution B in a bell-mouth manner, and drying it at 90°C for 4 hours after spinning to obtain a loose layer with good plasticity. Specifically, in this step: the bell-mouth manner of the electrospinning operation is as follows: the electrospinning solution B is placed in two 20ml syringes, and sprayed at a flow rate of 1.4ml / h to 12cm on both sides of the middle rotating meat head through a propulsion pump, while giving the two syringe needles a positive and negative pressure of 7KV respectively. After spinning, drying it at 80°C for 4 hours, thus obtaining a loose layer that can be arbitrarily shaped and has a cotton-like shape;

[0056] 3. Preparation of composite materials:

[0057] S1. Spread the obtained dense layer flat on the stainless steel interface, use an ultrasonic welding machine with a pressure of 0.2 MPa and a welding time of 0.2 s / point, and weld the obtained loose layer on the dense layer at a distance of 0.2 mm per point to obtain a composite material for alveolar bone repair.

[0058] The preparation method of amino nano-hydroxyapatite described in Example 1 includes the following specific steps:

[0059] (1) Dissolve calcium nitrate in purified water (mass ratio 1:2), then adjust the pH to 10.5 with ammonia water and heat to boiling in an electric furnace;

[0060] (2) After heating to boiling, slowly add 20% ammonium hydrogen phosphate solution (wherein the mass ratio of calcium nitrate to ammonium hydrogen phosphate solution is 1.5:1) under stirring at 200 rpm. The addition time is controlled within 15 minutes. After the addition is completed, continue the reaction for 5 hours;

[0061] (3) After the reaction is completed, the mixture is placed in a muffle furnace and calcined for 6 hours at 800°C to obtain amino nano-hydroxyapatite.

[0062] Example 2

[0063] A composite material for alveolar bone repair, characterized in that the composite material is ultrasonically welded from a dense layer having a soft tissue barrier function and a loose layer having a bone tissue regeneration guiding function; wherein: the dense layer is a fiber membrane formed by stacking nanofibers, which is formed by electrostatic spinning of a polyester medical polymer material; the loose layer serves as a scaffold material for bone repair, which is formed by electrostatic spinning of a composite scaffold material; the composite scaffold material is bonded by a nanoscale inorganic filler material (amino nanoscale hydroxyapatite, particle size: 100-300nm) and a polyester medical polymer material (poly(L-lactide-co-glycolide) (85:15, intrinsic viscosity: 2.5-3.5dL / g).

[0064] The method for preparing a composite material for alveolar bone repair described in the above embodiment 2 comprises the following specific steps:

[0065] 1. Preparation of dense layer:

[0066] S1. Dissolving a polyester medical polymer material (poly(L-lactide-co-glycolide)) in chloroform to a concentration of 16 wt %. Then, adding DMSO (the same mass as the chloroform) and stirring uniformly to form a spinning solution A.

[0067] S2. The obtained spinning solution A is loaded into a syringe with a needle aperture of 0.4 mm, an injection speed of 1.5 ml / h, a voltage of 25 kV, and a receiving distance of 18 cm for electrospinning to obtain an electrospun membrane, which is a polyester medical polymer membrane; the electrospinning technology in this step adopts a needle spinning method, and the receiving interface is a flat receiving surface with a diameter of 10 cm;

[0068] S3, drying the obtained electrospun membrane at 105° C. for 2 hours, and then stacking the obtained electrospun membranes to obtain a dense layer;

[0069] 2. Preparation of loose layer:

[0070] S1. Dry the nanoscale inorganic filler material (amino nanoscale hydroxyapatite) in vacuum at 50° C. for 48 hours (the vacuum degree is below 200 bar), dissolve the dried material in chloroform (the mass ratio of the nanoscale inorganic filler material to chloroform is 1:3), and then slowly introduce HBr gas under stirring at room temperature for 3 hours to obtain a halogenated nanoscale inorganic filler material;

[0071] S2. Dissolving a certain amount of poly(L-lactide-co-glycolide) in chloroform to obtain a chloroform solution containing 15 wt% of poly(L-lactide-co-glycolide), referred to as a dissolving solution; adding the dissolving solution dropwise to the halogenated nanoscale inorganic filler material obtained above (note: the molar ratio of amino nanoscale hydroxyapatite to poly(L-lactide-co-glycolide) is 1:1), and then refluxing and stirring for 10 hours; after refluxing and stirring, rotary evaporation is performed to remove the chloroform, and then the bonded product is rinsed with purified water for 2 hours and dried at 80°C for 4 hours to obtain a bonded product of the nanoscale inorganic filler material and the polyester medical polymer material, which is a composite stent material;

[0072] S3, dissolving the obtained composite scaffold material in chloroform and stirring evenly, wherein the concentration of the composite scaffold material is 18 wt %, and then adding DMSO of the same mass as the chloroform and stirring evenly to obtain a spinning solution B;

[0073] S4, electrospinning the obtained spinning solution B by centrifugal spinning, and drying it at 120°C for 2 hours after spinning to obtain a loose layer with good plasticity; specifically, in this step: the electrospinning operation centrifugal spinning method is as follows: the electrospinning solution B is placed in a 20ml syringe and ejected at a flow rate of 1.2ml / h through a propulsion pump, while applying a voltage of 8Kv to the nozzle, and a rotatable receiving disk is set 3cm away from the nozzle, with a diameter of 10cm and a speed of 16rpm. After spinning, drying it at 120°C for 2 hours to obtain a loose layer that can be arbitrarily shaped and has a cotton-like shape;

[0074] 3. Preparation of composite materials:

[0075] S1. Spread the obtained dense layer flat on the stainless steel interface, use an ultrasonic welding machine with a pressure of 0.2 MPa and a welding time of 0.2 s / point, and weld the obtained loose layer on the dense layer at a distance of 0.2 mm per point to obtain a composite material for alveolar bone repair.

[0076] Example 3

[0077] A composite material for alveolar bone repair, characterized in that the composite material is formed by ultrasonic welding of a dense layer having a soft tissue barrier function and a loose layer having a bone tissue regeneration guiding function; wherein: the dense layer is a fiber membrane formed by stacking nanofibers, which is formed by electrostatic spinning of a polyester medical polymer material; the loose layer serves as a scaffold material for bone repair, which is formed by electrostatic spinning of a composite scaffold material; the composite scaffold material is formed by bonding a nanoscale inorganic filler material (silicon salt-doped calcium carbonate, particle size: 20-200μm) and a polyester medical polymer material (poly(L-lactide-co-ε-caprolactone)) (70:30, intrinsic viscosity: 1.3-1.8dL / g).

[0078] The method for preparing a composite material for alveolar bone repair described in the above embodiment 3 comprises the following specific steps:

[0079] 1. Preparation of dense layer:

[0080] S1. Dissolve a polyester medical polymer material (poly(L-lactide-co-ε-caprolactone)) in chloroform to a concentration of 20 wt %, then add DMSO (the same mass as the chloroform) and stir evenly to form a spinning solution A.

[0081] S2. The obtained spinning solution A is loaded into a syringe with a needle aperture of 0.4 mm, an injection speed of 2.0 ml / h, a voltage of 15 kV, and a receiving distance of 18 cm for electrospinning to obtain an electrospun membrane, which is a polyester medical polymer membrane; the electrospinning technology in this step adopts a needle spinning method, and the receiving interface is a flat receiving surface with a diameter of 8 cm;

[0082] S3, drying the obtained electrospun membrane at 105° C. for 2 hours, and then stacking the obtained electrospun membranes to obtain a dense layer;

[0083] 2. Preparation of loose layer:

[0084] S1. The nano-scale inorganic filler material (silicon salt-doped calcium carbonate) is vacuum dried at 60° C. for 36 hours (the vacuum degree is below 200 bar), and after drying, the material is dissolved in chloroform (the mass ratio of the nano-scale inorganic filler material to chloroform is 1:3), and then HBr gas is slowly introduced into the mixture under stirring at room temperature for 3 hours to obtain a halogenated nano-scale inorganic filler material;

[0085] S2. A certain amount of poly (L-lactide-co-ε-caprolactone) is dissolved in chloroform to obtain a chloroform solution containing 20 wt% of poly (L-lactide-co-ε-caprolactone), which is referred to as a dissolving solution; the dissolving solution is added dropwise to the halogenated nanoscale inorganic filler material obtained above (note: the molar ratio of silicate-doped calcium carbonate to poly (L-lactide-co-ε-caprolactone) is 1:1), and then refluxed with stirring for 12 hours; after reflux and stirring, the chloroform is removed by rotary evaporation, and the bonded product is rinsed with purified water for 2 hours and dried at 80° C. for 4 hours to obtain a bonding product of the nanoscale inorganic filler material and the polyester medical polymer material, which is a composite stent material;

[0086] S3, dissolving the obtained composite scaffold material in chloroform and stirring evenly, wherein the concentration of the composite scaffold material is 25 wt %, and then adding DMSO of the same mass as the chloroform and stirring evenly to obtain a spinning solution B;

[0087] S4, electrospinning the obtained spinning solution B by centrifugal spinning, and drying it at 120°C for 2 hours after spinning to obtain a loose layer with good plasticity; specifically, in this step: the electrospinning operation centrifugal spinning method is as follows: the electrospinning solution B is placed in a 20ml syringe and ejected at a flow rate of 1.4ml / h through a propulsion pump, while applying a voltage of 8Kv to the nozzle, and a rotatable receiving disk is set at 5cm away from the nozzle, with a diameter of 10cm and a speed of 16rpm. After spinning, drying it at 105°C for 2 hours to obtain a loose layer that can be arbitrarily shaped and has a cotton-like shape;

[0088] 3. Preparation of composite materials:

[0089] S1. Spread the obtained dense layer flat on the stainless steel interface, use an ultrasonic welding machine with a pressure of 0.2 MPa and a welding time of 0.2 s / point, and weld the obtained loose layer on the dense layer at a distance of 0.2 mm per point to obtain a composite material for alveolar bone repair.

[0090] test:

[0091] 1. Chemical performance test:

[0092] (1) Solvent residue test: The composite materials for alveolar bone repair obtained in Examples 1-3 were dissolved in dichloromethane (sample concentration 5%), and the residual solvent was detected using gas chromatography. The test results are shown in Table 1 below.

[0093] Table 1 shows the test results of solvent residue of the composite materials obtained in Examples 1-3 above.

[0094] Serial number Test items Allowable limit / % Residue / % Example 1 Hexafluoroisopropanol residue 0.089 Not detected Example 2 DMSO residue 0.5 0.004 Example 3 DMSO residue 0.5 Not detected

[0095] It can be seen from the test results in Table 1 that the composite material for alveolar bone repair prepared by the present invention has a low residual solvent content and can be used with confidence.

[0096] (2) Moisture content test: The composite materials for alveolar bone repair prepared in the above Examples 1-3 were tested for moisture using the Karl Fischer method. The test was conducted three times in a row under an ambient humidity of less than RH40%, and the average value was taken. To ensure the storage stability of the prepared product, the moisture content of the product should not be greater than 10%. For specific test results, see Table 2 below.

[0097] Table 2 is the test results of the moisture content of the composite materials obtained by combining the materials in Examples 1-3

[0098] name Moisture content / % Example 1 2.1 Example 2 1.3 Example 3 1.6

[0099] It can be seen from the test results in Table 2 that the composite material for alveolar bone repair prepared in the present invention has a sufficient water content and can meet the requirements of long-term stable storage.

[0100] 2. Physical performance test:

[0101] (1) pH test: The products obtained in Examples 1-3 were added to an extract (purified water) at a ratio of 0.1 g / ml, and the mixture was extracted at (37±1)°C for 72 hours. The supernatant was taken to obtain a test solution, and the pH value was determined according to the pH determination method in General Chapter 0631 of the Chinese Pharmacopoeia (Part 4, 2020 Edition). The results were between 6 and 8, which met the standard. The test results of Examples 1-3 are shown in Table 3 below.

[0102] Table 3 is the pH test results of the products obtained in Examples 1-3 of the present invention

[0103]

[0104]

[0105] It can be seen from the test results in Table 3 that the pH value of the composite material for alveolar bone repair prepared in the present invention meets the requirements.

[0106] (2) Dense layer tensile strength test: The dense layer of the composite material for alveolar bone repair prepared in Examples 1-3 was cut out and cut into 1 cm*2 cm membrane sheets, and then a universal testing machine was used for tensile testing. The speed of the testing machine was set to 10 nm / min. The machine was started and a tensile test was performed. The test results are shown in Table 4 below.

[0107] Table 4 shows the tensile strength test results of the dense layer in the composite materials obtained in Examples 1-3

[0108] name Tensile strength / N Example 1 14.2 Example 2 14.4 Example 3 14.1 Absorbable collagen membrane 8.6

[0109] The dense layer of the present invention acts as a soft tissue barrier, while also providing an independent space for new tissue to form bones. This type of soft tissue barrier membrane requires suture to the native tissue during implantation and maintains a specific post-implantation morphology, thus requiring a certain tensile strength. As can be seen from the test data in Table 4, the dense layer of the present invention exhibits superior mechanical properties to absorbable collagen membranes.

[0110] (3) Compressive strength test: The composite materials for alveolar bone repair prepared in Examples 1-3 were subjected to a compressive strength test. The test results are shown in Table 5 below.

[0111] Table 5 shows the compressive strength test results of the composite materials prepared in Examples 1-3.

[0112] name Compressive strength / Mpa Example 1 5.1 Example 2 4.7 Example 3 4.9 Hydroxyapatite material 5.2 PLGA filler 2.1

[0113] The composite material for alveolar bone repair prepared by the present invention bonds organic polymer materials with hydroxyapatite for the purpose of improving its degradability and plasticity. This approach may have the risk of decreased mechanical properties, but from the test data in Table 5 above, it can be seen that the compressive strength of the product prepared by the present invention is not significantly lower than that of the hydroxyapatite material.

[0114] 3. Biological evaluation research:

[0115] (1) Cytotoxicity: The composite materials prepared in Examples 1-3 were extracted at a ratio of 0.1 g / ml (the extract was MEM culture medium containing 10% fetal bovine serum) at 37°C for 24 hours, and then a cytotoxicity test was performed with reference to the MTT method in GB / T16886.5. The relative cell viability values ​​of Examples 1-3 were 87.9%, 86.4%, and 88.2%, respectively, indicating no potential cytotoxicity.

[0116] (2) Delayed-type hypersensitivity reaction: The products prepared in Examples 1-3 were respectively prepared into extracts with 0.9% sodium chloride injection and cottonseed oil. The extracts were intradermally injected into 10 albino guinea pigs, and then occluded with patching to induce delayed-type hypersensitivity reaction. Figure 1 As shown, Figure 1 Middle markers: 1 - head, 2 - 0.1 ml intradermal injection site, 3 - hairless medial shoulder blade, 4 - tail.

[0117] Conclusion: The animals produced a reaction with a level greater than "0" within 24 hours and 48 hours of observation after stimulation, indicating that the product prepared by the present invention did not induce delayed-type hypersensitivity reaction in albino guinea pigs.

[0118] (3) In vitro degradation performance study: After soaking the materials obtained in Examples 1-3 with physiological saline, the loose layer was compressed and placed in a conical flask filled with simulated body fluid (extraction ratio 0.1 g / ml). The material was placed at 37°C and in a constant temperature shaker at 100 rpm. The material changes were observed every week (because nano-inorganic materials cannot simulate in vitro degradation performance, the end time of degradation is the completion of degradation of medical polymer materials). The test results are shown in Table 6 below.

[0119] Table 6 shows the results of in vitro degradation performance test

[0120]

[0121]

[0122] Compared to natural inorganic materials, which primarily provide inorganic nutrients to newly formed bone and are slowly absorbed, their degradation cycle is over two years. Compared to existing soft tissue barrier membranes, existing soft tissue barrier membranes degrade rapidly, unable to maintain long-term bone formation, and their degradation rate is mismatched with the bone formation rate. As shown in the data in Table 6, the composite material for alveolar bone repair prepared by the present invention has a degradation cycle of between 14 and 20 weeks, while the alveolar bone repair cycle is typically around three months. Therefore, the present invention provides a new material that matches the bone formation rate of newly formed bone, further promoting alveolar bone growth.

[0123] The above preferred embodiments of the present invention are only used to explain the present invention and are not used to limit the present invention. Any obvious changes or modifications derived from the technical solution of the present invention are still within the scope of protection of the present invention.

Claims

1. A composite material for alveolar bone repair, characterized in that: The composite material consists of a dense layer having a soft tissue barrier function and a loose layer having a function of guiding bone tissue regeneration; The dense layer is a fiber membrane formed by stacking nanofibers, which is made by electrospinning polyester medical polymer materials; the loose layer is a scaffold material for bone repair, which is made by electrospinning a composite scaffold material; the composite scaffold material is bonded by nano-scale inorganic filler materials and polyester medical polymer materials; The preparation method of the composite material comprises the following steps:

1. Preparation of dense layer: S1, dissolving a polyester medical polymer material in a first solvent, then adding a second solvent, and stirring evenly to form a spinning solution A; S2, electrospinning the spinning solution A to obtain an electrospinning membrane; S3, drying the electrospun membrane, and then stacking to obtain a dense layer; 2. Preparation of loose layer: S1. Drying the nanoscale inorganic filler material, then dissolving it in an organic solvent, and introducing HX gas to react to obtain a halogenated nanoscale inorganic filler material; wherein X is selected from one of Cl, Br, and I; S2, dissolving the polyester medical polymer material in the organic solvent to obtain a solution; adding the solution dropwise to the halogenated nanoscale inorganic filler material, and then refluxing and stirring; after refluxing and stirring, removing the organic solvent, washing, and drying the resulting product to obtain a bonding product of the nanoscale inorganic filler material and the polyester medical polymer material, which is a composite stent material; S3, dissolving the composite scaffold material, then adding a third solvent, and stirring evenly to obtain a spinning solution B; S4, electrospinning the spinning solution B by using a bell-mouth or centrifugal spinning method, and drying after spinning to obtain a cotton-like loose layer with good plasticity; 3. Preparation of composite materials: S1. Ultrasonic welding the loose layer to the dense layer to obtain a composite material for alveolar bone repair.

2. The composite material for alveolar bone repair according to claim 1, characterized in that: The fiber diameter of the dense layer is 10 to 10000 nm, and the thickness of the dense layer is 0.1 to 0.5 cm.

3. The composite material for alveolar bone repair according to claim 1, characterized in that: The polyester medical polymer material is selected from one of poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(L-lactide-co-ε-caprolactone) and their modified products; The nanoscale inorganic filling material is selected from one of aminohydroxyapatite, silicate-doped calcium carbonate, β-tricalcium phosphate, bioactive glass, and biphasic calcium phosphate ceramics; The intrinsic viscosity of the polyester medical polymer material is 1.3-7.0 dL / g.

4. The composite material for alveolar bone repair according to claim 1, characterized in that:

1. Preparation of dense layer: S1. Dissolving a polyester medical polymer material in a first solvent to a concentration of 16-20 wt %, then adding a second solvent and stirring uniformly to form a spinning solution A; The first solvent is chloroform; the second solvent is selected from one of dimethylbenzamide, hexafluoroisopropanol, DMSO, trifluoroethanol, tetrahydrofuran, DMF, and toluene; and the mass ratio of the first solvent to the second solvent is 1:(1-2).

5. The composite material for alveolar bone repair according to claim 1, characterized in that:

2. Preparation of the loose layer: Step S1, vacuum drying the nanoscale inorganic filler material at 40-60°C for 24-48 hours, then dissolving it in an organic solvent, slowly introducing HX gas at room temperature to react for 1-3 hours to obtain a halogenated nanoscale inorganic filler material; wherein the organic solvent is chloroform, and the mass ratio of the nanoscale inorganic filler material to the organic solvent is 1:(2-5).

6. The composite material for alveolar bone repair according to claim 1, characterized in that:

2. Preparation of the loose layer: Step S2, dissolving the polyester medical polymer material in chloroform to obtain a solution containing 10-20 wt% of the polyester medical polymer material; then adding the solution dropwise to the halogenated nanoscale inorganic filler material and reflux stirring for 8-12 hours. After the reaction, the chloroform is removed by rotary evaporation, and the resulting product is rinsed with purified water for 2-3 hours, and dried at 70-90°C for 2-4 hours to obtain a bonding product of the nanoscale inorganic filler material and the polyester medical polymer material; wherein the molar ratio of the halogenated nanoscale inorganic filler material to the polyester medical polymer material is 1:(1-2).

7. The composite material for alveolar bone repair according to claim 1, characterized in that:

2. Preparation of the loose layer: Step S3, dissolving the obtained bonding product in chloroform, and the concentration of the bonding product is 18-26wt%, then adding a third solvent, and stirring evenly to obtain a spinning solution B; wherein the mass ratio of the third solvent to the chloroform is 1: (1-2), and the third solvent is selected from one of dimethylbenzamide, hexafluoroisopropanol, DMSO, trifluoroethanol, tetrahydrofuran, DMF, and toluene.

8. The composite material for alveolar bone repair according to claim 1, characterized in that:

2. Preparation of the loose layer: Step S4, electrospinning the spinning solution B by using a bell-mouth or centrifugal spinning method, and drying the spinning solution at 80-120°C for 2-4 hours to obtain a cotton-like loose layer with good plasticity.

9. The composite material for alveolar bone repair according to claim 1, characterized in that:

3. Preparation of composite materials: S1. Spread the dense layer flat on the stainless steel interface, use an ultrasonic welding machine with a pressure of 0.1-0.3 MPa and a welding time of 0.1-0.3 s / point, and weld the loose layer on the dense layer at a distance of 0.1-0.3 mm per point to obtain a composite material for alveolar bone repair.

Images