CN115054743A - Barrier membrane capable of promoting alveolar bone regeneration and preparation method thereof - Google Patents
Barrier membrane capable of promoting alveolar bone regeneration and preparation method thereof Download PDFInfo
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/043—Proteins; Polypeptides; Degradation products thereof
- A61L31/044—Collagen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/02—Inorganic materials
- A61L31/028—Other inorganic materials not covered by A61L31/022 - A61L31/026
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
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- C—CHEMISTRY; METALLURGY
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A61L2400/00—Materials characterised by their function or physical properties
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- A—HUMAN NECESSITIES
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
Abstract
The invention discloses a barrier film capable of promoting alveolar bone regeneration and a preparation method thereof, wherein the barrier film is of a double-layer film structure and comprises an upper film layer of a single-component structure and a lower film layer of a double-component structure; the upper film layer is formed by laying three collagen films, and the lower film layer is formed by compounding collagen and hydroxyapatite; the preparation method comprises laminating upper membrane made of porcine or bovine small intestine submucosa or pericardium on lower membrane made of porcine or bovine skin or tenascin and nano-hydroxyapatite, pressing, and cross-linking with cobalt 60 radiation source. The barrier membrane of the invention does not produce immunogenic reaction; the double-layer structure formed by pressing and crosslinking has excellent mechanical property and space maintenance effect; and the lower membrane layer can be well embedded with the tooth defect area through the molding of a customized mold, so that the barrier membrane is prevented from shifting, no chemical cross-linking agent is used, no inflammatory reaction is generated, and the application prospect is good.
Description
Technical Field
The invention relates to the field of biological repair materials, in particular to a barrier film capable of promoting alveolar bone regeneration and a preparation method thereof.
Background
With the continuous development and maturity of the oral implant technology, the problem of tooth loss repair is successfully solved. However, insufficient alveolar bone mass following a tooth loss is a limitation and challenge in oral implant techniques. To solve this problem, guided bone regeneration techniques have been developed. The guided bone regeneration technology is to form a space for osteoprogenitor cells to grow and proliferate in a tooth loss area by utilizing a barrier membrane, so that the bone mass of alveolar bone is increased to meet the requirement of later dental implantation.
Currently, the clinical barrier membranes are classified into non-tissue compatible materials and tissue compatible materials according to whether they are tissue compatible or not. The materials which are not compatible with tissues are polytetrafluoroethylene membrane materials and titanium membrane materials, and the materials have excellent mechanical property and good space maintenance and are a good news of dental implanters once, but the materials are not compatible with tissues and still exist after the growth cycle of alveolar bones is finished, so the materials need to be removed by secondary operations, and the risk of secondary infection is brought to patients. Thus, materials that are compatible with tissue are currently preferred in the market. The material compatible with the tissue is gradually decomposed by enzyme in body fluid in the process of promoting the growth of the alveolar bone; the decomposed components are partially absorbed by tissues and partially discharged out of the body along with body fluid.
The existing materials compatible with tissues mainly comprise polylactic acid materials and animal-derived collagen materials. However, the polylactic acid material can inhibit the growth of alveolar bone due to the strong acidity of the degradation product lactic acid, and the animal-derived collagen material on the market at present has poor mechanical properties and a fast degradation period, and cannot meet the requirement of alveolar bone growth. In order to solve the problem, the degradation characteristics and mechanical properties of animal-derived materials are improved by adding a chemical cross-linking agent, but the chemical cross-linking agent is difficult to remove, so that the problem that the residual cross-linking agent is easy to cause inflammatory reaction exists. In addition, the existing barrier membrane is difficult to position when in use, the barrier membrane can cause the loss of bone grafting space and the leakage of bone grafting materials, and the expected bone grafting effect can not be met, so that certain auxiliary measures are required to position in clinical application, the use is troublesome, and the embedding degree with a tooth defect area can not be ensured.
Disclosure of Invention
In view of the above problems, the present invention provides a barrier membrane for promoting alveolar bone regeneration, which does not contain a chemical cross-linking agent and does not generate an inflammatory reaction, and a method for preparing the same; has good mechanical property and proper degradation time, and can be well embedded with the tooth defect area to prevent the barrier membrane from shifting. The specific technical scheme is as follows:
firstly, the invention provides a barrier membrane capable of promoting alveolar bone regeneration, which is of a double-layer membrane structure and comprises an upper membrane layer of a single-component structure and a lower membrane layer of a double-component structure; the upper film layer is formed by laying three layers of collagen films, and the lower film layer is formed by compounding collagen and hydroxyapatite.
Preferably, the collagen membrane of the upper membrane layer and the collagen of the lower membrane layer are both made of I-type animal collagen tissues; wherein, the three collagen films of the upper film layer are prepared from porcine or bovine small intestine submucosa or pericardium; the collagen of the lower membrane layer is prepared from the skin or tendon of pig or cattle.
Preferably, the thickness of the upper film layer is 0.06-0.45 mm, and the thickness of the three collagen films is 0.02-0.15 mm; the thickness of lower rete is 0.05 ~ 0.45mm, and it is the specific structure of customization mould shaping.
Preferably, the lower membrane layer is formed by blending the protein component A and the nano-hydroxyapatite component B and then pouring the mixture into a customized mould for freeze forming; the protein component A is formed by mixing collagen and acetic acid according to a feed-liquid ratio of 1: 50-1: 100; the nano-hydroxyapatite component B is formed by mixing hydroxyapatite and polyethylene glycol according to a material-liquid ratio of 1: 100-1: 300.
The invention further provides a preparation method of the barrier membrane capable of promoting alveolar bone regeneration, which comprises the following steps:
s1: preparing an upper film layer: cleaning porcine or bovine small intestinal submucosa or pericardium, degreasing, deproteinizing, removing viruses, cutting into a certain size, laying and stacking 3 layers, dehydrating and drying to obtain an upper membrane layer for later use;
s2: preparing a lower film layer: preparing collagen protein component A from skin or tendon of pig or cattle, mixing with nanometer hydroxyapatite component B, freezing and molding in a mold, dewatering, and drying to obtain lower membrane layer;
s3: and (3) crosslinking: and laminating the prepared upper membrane on the lower membrane, performing combined pressing under the pressure of 30-40 tons, and then performing radiation crosslinking in a cobalt 60 radiation source with the radiation dose of 15-30 kGy for 30 min-3 h to obtain the barrier membrane capable of promoting alveolar bone regeneration.
As a preferred technical solution, step S1 is to prepare an upper film layer:
the degreasing reagent is mixed solution of isopropanol, normal hexane, trichloromethane and methanol; preferably, the mixed solution of trichloromethane and methanol is mixed in a volume ratio of 2-3: 1-2, preferably 2:1 or 3: 2; the operation method comprises the step of soaking the small intestine submucosa or the pericardium of the pig or the cattle in the degreasing reagent for 10-36 h, preferably 18-32 h, more preferably 20-30 h, and most preferably 24 h.
The deproteinizing reagent is hydrogen peroxide solution, sodium hypochlorite solution or sodium dodecyl sulfate solution; preferably a sodium hypochlorite solution or a sodium dodecyl sulfate solution; further preferably a sodium lauryl sulfate solution; the mass fraction concentration of the hydrogen peroxide solution is 10-30%, preferably 15-25%, more preferably 15-20%, and most preferably 20%; the mass fraction concentration of the sodium hypochlorite solution is 0.1-3%, preferably 0.5-2%, more preferably 1-1.5%, and most preferably 1.5%; the mass fraction concentration of the sodium dodecyl sulfate solution is 0.1-2%, preferably 0.5-2%, more preferably 1-1.5%, and most preferably 1%; (ii) a The operation method comprises the step of placing the small intestine submucosa or the pericardium of the pig or the cattle in the decellularization reagent for ultrasonic soaking for 3-16 h, preferably 5-12 h, more preferably 6-10 h, and most preferably 8 h.
The virus removing reagent is sodium hydroxide solution, oxalic acid solution or ethanol solution, preferably oxalic acid solution or ethanol solution, and more preferably oxalic acid solution; the concentration of the sodium hydroxide solution is 0.5-2 mol/L, preferably 0.5-1.5 mol/L, more preferably 1-1.5 mol/L, and most preferably 1.5 mol/L; the mass fraction concentration of the oxalic acid solution is 8-20%, preferably 10-20%, more preferably 15-20%, and most preferably 15%; the volume fraction concentration of the ethanol solution is 70-95%, and the preference is 75%; the operation method comprises the step of soaking the porcine or bovine small intestinal submucosa or pericardium in the virus removing reagent for 1-10 hours, preferably 2-8 hours, more preferably 4-6 hours, and most preferably 6 hours.
As a preferred technical scheme, the step S2 of preparing the lower membrane layer includes two links of collagen purification and hydroxyapatite composition; the specific operation is as follows:
s2-1: and (3) purification: cutting the cleaned skin or tendon of the pig or the cattle into slices with the thickness of 1-3 mm, preferably 2 mm; putting into 0.1% -5% acetic acid or hydrochloric acid solution; adding trypsin, pepsin or fig enzyme, stirring for 6-36 h at the temperature of 2-8 ℃, and carrying out enzymolysis; and then filtering out particles by using a stainless steel net with 20-40 meshes, and adding 0.5-4 mol/L sodium hydroxide solution for protein precipitation to obtain collagen for later use. The concentration of the acetic acid solution is preferably 0.5 to 3%, more preferably 1 to 2%, and most preferably 1.5%; the concentration of the hydrochloric acid solution is preferably 1 to 3 percent, more preferably 1.5 to 3 percent, and most preferably 2 percent; the enzymolysis is preferably carried out by adopting a fig enzyme, and the enzymolysis is preferably carried out by stirring for 24 hours at 4 ℃; the concentration of the sodium hydroxide solution is preferably 2-3 mol/L, and more preferably 3 mol/L.
S2-2: compounding: dissolving the precipitated collagen in 0.1-2% acetic acid according to the feed-liquid ratio of 1: 50-1: 100, stirring by using a stirrer at the rotation speed of 200-500 rpm for 2-4 h to form a protein component A; mixing nano hydroxyapatite according to a material-liquid ratio of 1: 100-1: 300 is added into the polyethylene glycol solution, and is stirred by a stirrer at the rotating speed of 100rpm to 400rpm for 3h to 6h to form a nano hydroxyapatite component B; in order to enable the nano-hydroxyapatite to be more uniformly dispersed in the collagen liquid, adding the prepared nano-hydroxyapatite component B into the component A for 3-5 times, and stirring and blending by adopting a stirrer at the rotating speed of 200-500 rpm for 4-6 hours; after blending, pouring the mixture into a set mould for freeze forming, and dehydrating and drying to obtain a lower film layer. The ratio of collagen to acetic acid is preferably 1: 60-1: 80, more preferably 1: 70-1: 80, and most preferably 1: 75; the ratio of the nano-hydroxyapatite to the polyethylene glycol is preferably 1:150 to 1:250, more preferably 1:180 to 1:220, and most preferably 1: 200.
As a preferred technical scheme, the upper membrane layer is prepared in the step S1, and the lower membrane layer is prepared in the step S2, and the dehydration drying mode is vacuum freeze drying or ethanol gradient dehydration drying; wherein the technological parameters of the vacuum freeze drying are as follows: drying for 48-72 h at-45-30 ℃; gradient ethanol dehydration drying gradient is: 25 to 100 percent.
The invention has the beneficial effects that:
1) the barrier membrane of the invention adopts purified type I collagen, has low immunogenicity, and does not generate immunogenic reaction.
2) The barrier film is of a double-layer film structure, and the lower film layer of the barrier film is of a double-component structure formed by compounding collagen and hydroxyapatite, so that the barrier film is excellent in mechanical property and space maintenance effect; and the film layer is a specific structure formed by a customized die, can be well embedded with a tooth defect area, prevents the barrier film from shifting, and prevents the loss of a bone grafting space and the leakage of bone grafting materials.
3) The upper film layer of the barrier film is formed by laying three layers of collagen films, has soft texture, can be better attached to soft tissues and compatible with the tissues, avoids inflammation, and plays a good role in repairing and promoting wound repair.
4) After the upper film layer and the lower film layer of the barrier film are laminated, the barrier film is crosslinked together in a cobalt 60 radiation source without a chemical crosslinking agent, so that inflammatory reaction is further avoided.
Drawings
FIG. 1 is a diagram of a finished barrier membrane for promoting alveolar bone regeneration according to the present invention;
FIG. 2 is a view of a dental socket of a patient after extraction of a tooth in an application example of the present invention;
FIG. 3 is a diagram of a patient after implantation of a barrier membrane of the present invention in an example of use of the present invention;
FIG. 4 illustrates a first postoperative return repair of a patient in an example application of the present invention;
fig. 5 shows a second postoperative return repair of a patient in an application example of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail and completely with reference to the embodiments and the accompanying drawings.
Example 1
The embodiment is a barrier membrane capable of promoting alveolar bone regeneration, which has a double-layer membrane structure and comprises an upper membrane layer with a single-component structure and a lower membrane layer with a double-component structure; the upper film layer is formed by laying three collagen films, and the lower film layer is formed by compounding collagen and hydroxyapatite. The collagen membrane of the upper membrane layer and the collagen of the lower membrane layer are both made of I-type animal collagen tissues; wherein, the three collagen films of the upper film layer are prepared from the porcine small intestine submucosa; the collagen of the lower membrane layer is prepared from pigskin. The thickness of the upper film layer is about 0.1mm, and the thickness of the three collagen films is 0.04 mm; the thickness of the lower film layer is 0.2mm, which is a specific structure formed by a custom mold.
The preparation method of the barrier film specifically comprises the following steps:
s1: preparing an upper film layer: cleaning porcine or bovine small intestinal submucosa or pericardium, defatting, deproteinizing, removing virus, cutting into certain size, spreading and superposing 3 layers, dehydrating and drying to obtain upper membranous layer for later use. The degreasing reagent is a mixed solution of trichloromethane and methanol, and the volume ratio of the trichloromethane to the methanol is 2: 1; the operation method comprises the step of soaking the submucosa of the small intestine of the pig in the degreasing reagent for 24 hours. The deproteinizing reagent is sodium dodecyl sulfate solution with the mass fraction concentration of 1%; the operation method comprises the step of placing the mucous membrane of the small intestine of the pig in the deproteinizing reagent for ultrasonic soaking for 8 hours. The virus removing reagent is oxalic acid solution, and the mass fraction concentration of the oxalic acid solution is 15 percent; the operation method comprises the step of soaking the porcine small intestine submucosa in the virus removing reagent for 6 hours. The dehydration drying adopts vacuum freeze drying, and the technological parameters are as follows: drying at-45 deg.C for 48 h.
S2: preparing a lower film layer: preparing collagen protein component A from skin or tendon of pig or cattle, mixing with nanometer hydroxyapatite component B, freezing and molding in a mold, dewatering, and drying to obtain lower membrane layer; the specific operation is as follows:
s2-1: and (3) purification: cutting the cleaned pigskin into slices with the thickness of 2mm, putting the slices into 2% hydrochloric acid solution, adding the ficin, stirring for 24 hours at 4 ℃, and carrying out enzymolysis; then filtering out particles by using a 30-mesh stainless steel net, and adding 3mol/L sodium hydroxide solution for protein precipitation to obtain collagen for later use.
S2-2: compounding: dissolving the precipitated collagen in 2% acetic acid according to the feed-liquid ratio of 1:75, stirring by using a stirrer at the rotating speed of 500rpm for 3 hours to form a protein component A; adding the nano-hydroxyapatite into a polyethylene glycol solution according to a material-liquid ratio of 1:200, stirring by using a stirrer at a rotating speed of 300rpm for 5 hours to form a nano-hydroxyapatite component B; in order to enable the nano-hydroxyapatite to be uniformly dispersed in the collagen liquid, the prepared nano-hydroxyapatite component B is added into the component A for 3-5 times, and is stirred and blended by a stirrer at the rotating speed of 500rpm for 6 hours; after blending, pouring the mixture into a set mould for freeze forming, and dehydrating and drying to obtain the lower film layer. The dehydration drying adopts vacuum freeze drying, and the technological parameters are as follows: dried at-45 ℃ 72.
S3: and (3) crosslinking: the prepared upper membrane is stacked on the lower membrane, combined and pressed under 40 tons of pressure, and then placed in a cobalt 60 radiation source with the radiation dose of 25kGy for radiation crosslinking for 1h, so that the barrier membrane capable of promoting alveolar bone regeneration can be obtained, as shown in figure 1.
Example 2
In this embodiment, a barrier membrane capable of promoting alveolar bone regeneration is also prepared, in which the three collagen membranes of the upper membrane layer of the barrier membrane are prepared from bovine pericardium, and the collagen of the lower membrane layer is prepared from bovine tendon. The thickness of the upper film layer is about 0.4mm, and the thickness of the three collagen films is 0.13 mm; the thickness of the lower film layer is 0.45 mm. The preparation method comprises the following steps:
s1: preparing an upper film layer: cleaning porcine or bovine small intestinal submucosa or pericardium, defatting, deproteinizing, removing virus, cutting into certain size, spreading and superposing 3 layers, dehydrating and drying to obtain upper membranous layer for later use. Wherein the degreasing reagent is a mixed solution of trichloromethane and methanol, and the volume ratio of the mixed solution to the methanol is 3: 2; the operation method is to put the bovine pericardium into a degreasing reagent to be soaked for 32 h. The deproteinizing reagent is sodium hypochlorite solution, and the mass fraction concentration of the sodium hypochlorite solution is 1.5%; the operation method is that the bovine pericardium is placed in the deproteinized reagent to be soaked for 12 hours by ultrasonic wave. The virus removing reagent is ethanol solution, and the volume fraction concentration of the ethanol solution is 75 percent; the operation method is to put the bovine pericardium into the virus removing reagent to be soaked for 8 hours. The dehydration drying adopts vacuum freeze drying, and the technological parameters are as follows: drying at-45 deg.C for 60 h.
S2: preparing a lower film layer: preparing collagen extracted from skin or tendon of pig or cattle into component A, mixing with nanometer hydroxyapatite component B, pouring into a mold, freeze-molding, dehydrating, and drying to obtain lower membrane layer. The method specifically comprises the following steps:
s2-1: and (3) purification: cutting the cleaned tendon of cattle into slices with the thickness of 1 mm; putting into 3% acetic acid solution; adding trypsin, stirring at 8 deg.C for 32 hr, and performing enzymolysis; then filtering out particles by using a 20-mesh stainless steel net, and adding 4mol/L sodium hydroxide solution for protein precipitation to obtain collagen for later use.
S2-2: compounding: dissolving the precipitated collagen in 1% acetic acid according to the feed-liquid ratio of 1:80, stirring by a stirrer at the rotation speed of 400rpm for 4h to form a protein component A; adding the nano-hydroxyapatite into a polyethylene glycol solution according to a material-liquid ratio of 1:250, stirring by using a stirrer at a rotating speed of 300rpm for 5 hours to form a nano-hydroxyapatite component B; adding the nano-hydroxyapatite component B into the component A for 3-5 times, and stirring and blending by adopting a stirrer at the rotating speed of 500rpm for 4 hours; after blending, pouring the mixture into a set mould for freeze forming, and dehydrating and drying to obtain the lower film layer. The dehydration drying adopts vacuum freeze drying, and the technological parameters are as follows: drying at-45 deg.C for 70 h.
S3: and (3) crosslinking: and laminating the prepared upper membrane on the lower membrane, performing combined pressing under the pressure of 30 tons, and then performing radiation crosslinking in a cobalt 60 radiation source with the radiation dose of 30kGy for 30min to obtain the barrier membrane capable of promoting the regeneration of alveolar bone.
Example 3
In this embodiment, a barrier membrane capable of promoting alveolar bone regeneration is also prepared, where the upper membrane layer of the barrier membrane is prepared from bovine pericardium, and the collagen of the lower membrane layer is prepared from pigskin. The thickness of the upper film layer is 0.21mm, and the thickness of the three collagen films is 0.07mm respectively; the thickness of the lower film layer is 0.36 mm. The preparation method comprises the following steps:
s1: preparing an upper film layer: cleaning porcine or bovine small intestinal submucosa or pericardium, defatting, deproteinizing, removing virus, cutting into certain size, spreading and superposing 3 layers, dehydrating and drying to obtain upper membranous layer for later use. The degreasing reagent is a mixed solution of isopropanol and methanol, and the volume ratio of the mixture is 3: 1; the operation method is to put the bovine pericardium into the degreasing reagent and soak the bovine pericardium for 18 h. The deproteinizing reagent is hydrogen peroxide solution, and the mass fraction concentration of the hydrogen peroxide solution is 20%; the operation method is that the pericardium of the cattle is placed in the deproteinized reagent to be soaked for 10 hours by ultrasonic wave. The virus removing reagent is sodium hydroxide solution, and the concentration of the sodium hydroxide solution is 1.5 mol/L; the operation method is to put the pericardium of the cattle into the virus removing reagent to be soaked for 10 h. The dehydration drying adopts ethanol gradient dehydration drying, and the gradient of the dehydration drying is as follows: 25 to 100 percent.
S2: preparing a lower film layer: preparing collagen extracted from pigskin into a protein component A, mixing with a nano-hydroxyapatite component B, pouring into a mold for freeze forming, dehydrating and drying to prepare a lower membrane layer for later use; the specific operation is as follows:
s2-1: and (3) purification: cutting the cleaned pigskin into slices with the thickness of 3mm, and putting the slices into 2% hydrochloric acid solution; adding pepsin, stirring for 18h at the temperature of 8 ℃, and carrying out enzymolysis; then filtering out particles by using a 40-mesh stainless steel net, and adding 2mol/L sodium hydroxide solution for protein precipitation to obtain collagen for later use.
S2-2: compounding: dissolving the precipitated collagen in 2% acetic acid according to the feed-liquid ratio of 1:100, stirring by using a stirrer at the rotating speed of 500rpm for 2 hours to form a protein component A; nano hydroxyapatite is mixed according to a material-liquid ratio of 1:300, adding the mixture into a polyethylene glycol solution, stirring the mixture by a stirrer at the rotating speed of 400rpm for 3 hours to form a nano hydroxyapatite component B; adding the nano-hydroxyapatite component B into the component A for 3-5 times, and stirring and blending by adopting a stirrer at the rotating speed of 500rpm for 4 hours; after blending, pouring the mixture into a set mould for freeze forming, and dehydrating and drying to obtain the lower film layer. The dehydration drying adopts ethanol gradient dehydration drying, and the gradient of the dehydration drying is as follows: 25 to 100 percent.
S3: and (3) crosslinking: and laminating the prepared upper membrane on the lower membrane, performing combined pressing under the pressure of 30 tons, and then performing radiation crosslinking for 3 hours in a cobalt 60 radiation source with the radiation dose of 15kGy to obtain the barrier membrane capable of promoting the regeneration of alveolar bones.
Example 4 application example
This example is a post-extraction restorative treatment using the barrier membrane prepared in example 1. After the patient in this example had the teeth pulled out and the dental pit was filled, the barrier film prepared in the example was used to cover the wound and sutured; the gingival repair condition was followed up in time during the period, and the results are shown in fig. 2 to 5.
On the time axis, fig. 1 and 2 show the patient who is on the day of surgery, after extracting the teeth, filling the missing teeth and sewing the barrier film prepared in example 1, wherein the lower film layer of the barrier film is formed by a special mold and is covered on the fossa wound in a straddling manner for sewing. In the figure, it can be seen that there is edema in the gums of the patient after the operation.
FIG. 3 is the first follow-up of the patient one week after the operation, and it can be seen that the patient has the teeth with the suture in place, no redness and swelling of the gums, and good healing of the incision; the stitches are removed on the same day.
Fig. 4 is a second postoperative follow-up of the patient, and it can be seen that the gingival mucosa has healed completely and that the next preparation for tooth implantation can be undertaken.
According to the application example, the barrier film product disclosed by the invention can be well compatible with tissues, does not cause inflammation, can promote the growth and repair of alveolar bones and the healing of gingiva, and is beneficial to later-stage tooth implantation treatment. The barrier membrane adopts the purified type I collagen, so that the immunogenicity is low, and the immunogenic reaction is not generated; the film layer is a specific structure formed by a customized die, can be well embedded with a tooth defect area, prevents the barrier film from shifting, and prevents the loss of a bone grafting space and the leakage of bone grafting materials; the three collagen films of the upper film layer are soft, so that the three collagen films can be better attached to soft tissues and are compatible with the tissues, inflammation is avoided, and good repairing and wound repair promoting effects are achieved; and after the upper film layer and the lower film layer of the barrier film are laminated, the barrier film is crosslinked together in a cobalt 60 radiation source, and a chemical crosslinking agent is not used, so that inflammatory reaction is further avoided, and the barrier film has a very good application value.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. Furthermore, it should be understood that although the present specification describes embodiments, this does not include only one embodiment, and such description is for clarity only, and those skilled in the art should be able to make the specification as a whole, and the embodiments may be appropriately combined to form other embodiments understood by those skilled in the art.
Claims (10)
1. A barrier membrane for promoting alveolar bone regeneration, comprising:
the barrier film is of a double-layer film structure and comprises an upper film layer of a single-component structure and a lower film layer of a double-component structure;
the upper film layer is formed by laying three layers of collagen films,
the lower film layer is formed by compounding collagen and hydroxyapatite.
2. A barrier membrane for promoting alveolar bone regeneration according to claim 1, wherein:
the collagen membrane of the upper membrane layer and the collagen of the lower membrane layer are both made of I-type animal collagen tissues; wherein the content of the first and second substances,
the three collagen membranes of the upper membrane layer are prepared from porcine or bovine small intestine submucosa or pericardium;
the collagen of the lower membrane layer is prepared from the skin or tendon of pig or cattle.
3. A barrier membrane for promoting alveolar bone regeneration according to claim 2, wherein:
the thickness of the upper film layer is 0.06-0.45 mm, and the thickness of the three collagen films is 0.02-0.15 mm;
the thickness of lower rete is 0.05 ~ 0.5mm, and it is through customization mould shaping.
4. A barrier membrane for promoting alveolar bone regeneration according to claim 3, wherein:
the lower film layer is formed by blending a protein component A and a nano-hydroxyapatite component B and then pouring the mixture into a customized mould for freeze forming;
the protein component A is formed by mixing collagen and acetic acid according to a feed-liquid ratio of 1: 50-1: 100;
the nano hydroxyapatite component B is formed by mixing hydroxyapatite and polyethylene glycol according to a material-liquid ratio of 1: 100-1: 300.
5. A method for preparing a barrier film capable of promoting alveolar bone regeneration according to any one of claims 1 to 4, comprising: the method comprises the following steps:
s1: preparing an upper film layer: cleaning porcine or bovine small intestinal submucosa or pericardium, degreasing, deproteinizing, removing viruses, cutting into a certain size, laying and stacking 3 layers, dehydrating and drying to obtain an upper membrane layer for later use;
s2: preparing a lower film layer: preparing collagen protein component A from skin or tendon of pig or cattle, mixing with nanometer hydroxyapatite component B, freezing and molding in a mold, dewatering, and drying to obtain lower membrane layer;
s3: and (3) crosslinking: and laminating the prepared upper membrane on the lower membrane, performing combined pressing under the pressure of 30-40 tons, and then performing radiation crosslinking in a cobalt 60 radiation source with the radiation dose of 15-30 kGy for 30 min-3 h to obtain the barrier membrane capable of promoting alveolar bone regeneration.
6. The method for preparing a barrier membrane capable of promoting alveolar bone regeneration according to claim 5, wherein: step S1, preparing an upper film layer, wherein the degreasing reagent is a mixed solution of isopropanol, normal hexane, trichloromethane and methanol; the volume ratio of the mixed chloroform and methanol is 2-3: 1-2; the operation method comprises the step of soaking the small intestine submucosa or the pericardium of the pig or the cattle in the degreasing reagent for 10-36 hours.
7. The method for preparing a barrier membrane capable of promoting alveolar bone regeneration according to claim 5, wherein: s1, preparing an upper membrane layer, wherein the deproteinizing reagent is hydrogen peroxide solution, sodium hypochlorite solution or lauryl sodium sulfate solution; the mass fraction concentration of the hydrogen peroxide solution is 10-30%; the mass fraction concentration of the sodium hypochlorite solution is 0.1-3%; the mass fraction concentration of the sodium dodecyl sulfate solution is 0.1-2%; the operation method comprises the step of placing the small intestine submucosa or the pericardium of the pig or the cattle in the decellularization reagent for ultrasonic soaking for 3-16 h.
8. The method for preparing a barrier membrane capable of promoting alveolar bone regeneration according to claim 5, wherein: step S1, preparing an upper film layer, wherein the virus removing reagent is a sodium hydroxide solution, an oxalic acid solution or an ethanol solution; the concentration of the sodium hydroxide solution is 0.5-2 mol/L; the mass fraction concentration of the oxalic acid solution is 8-20%; the volume fraction concentration of the ethanol solution is 70-95%; the operation method comprises the step of soaking the small intestine submucosa or the pericardium of the pig or the cattle in the endotoxin removing reagent for 1-10 hours.
9. The method for preparing a barrier membrane capable of promoting alveolar bone regeneration according to claim 5, wherein: step S2, preparing a lower membrane layer, which comprises two links of collagen purification and hydroxyapatite compounding; the specific operation is as follows:
s2-1: and (3) purification: cutting the cleaned skin or tendon of the pig or the cattle into slices with the thickness of 1-3 mm, putting the slices into 0.1-5% acetic acid or hydrochloric acid solution, adding trypsin, pepsin or ficin, and stirring for 6-36 hours at the temperature of 2-8 ℃; then filtering out particles by using a stainless steel net with the mesh of 20-40, and adding 0.5-4 mol/L sodium hydroxide solution for protein precipitation to obtain collagen for later use;
s2-2: compounding: dissolving the precipitated collagen in 0.1-2% acetic acid according to the feed-liquid ratio of 1: 50-1: 100, stirring by using a stirrer at the rotation speed of 200-500 rpm for 2-4 h to form a protein component A;
mixing nano hydroxyapatite according to a material-liquid ratio of 1: 100-1: 300 is added into the polyethylene glycol solution, and is stirred by a stirrer at the rotating speed of 100rpm to 400rpm for 3h to 6h to form a nano hydroxyapatite component B;
adding the nano-hydroxyapatite component B into the component A for 3-5 times, and stirring and blending by adopting a stirrer at the rotation speed of 200-500 rpm for 4-6 hours; after blending, pouring the mixture into a set mould for freeze forming, and dehydrating and drying to obtain the lower film layer.
10. The method for preparing a barrier membrane capable of promoting alveolar bone regeneration according to claim 5, wherein: step S1, preparing an upper membrane layer and step S2, wherein the dehydration drying mode is vacuum freeze drying or ethanol gradient dehydration drying; wherein the technological parameters of the vacuum freeze drying are as follows: drying for 48-72 h at-45-30 ℃; gradient ethanol dehydration drying gradient is: 25 to 100 percent.
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