CN115054743B - 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 PDF

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CN115054743B
CN115054743B CN202210789751.0A CN202210789751A CN115054743B CN 115054743 B CN115054743 B CN 115054743B CN 202210789751 A CN202210789751 A CN 202210789751A CN 115054743 B CN115054743 B CN 115054743B
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membrane layer
collagen
layer
membrane
pig
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CN115054743A (en
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许力心
孙慧
齐迎珍
蔡飞翔
魏雪倩
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Xiling Zhenjiang Medical Technology Co ltd
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Xiling Zhenjiang Medical Technology Co ltd
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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
    • 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
    • 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
    • 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
    • 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
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/06—Preparation of peptides or proteins produced by the hydrolysis of a peptide bond, e.g. hydrolysate products
    • 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
    • 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
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • 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
    • 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 membrane capable of promoting alveolar bone regeneration and a preparation method thereof, wherein the barrier membrane 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 membrane layer is formed by paving three layers of collagen membranes, and the lower membrane layer collagen is formed by compounding hydroxyapatite; the preparation method comprises laminating upper membrane layer made of pig or cattle intestinal submucosa or pericardium on lower membrane layer made of pig or cattle skin or tenascin and nanometer hydroxyapatite, pressing, and crosslinking by cobalt 60 radiation source. The barrier membrane of the present invention does not produce an immunogenic response; the double-layer structure formed by compression crosslinking has excellent mechanical property and excellent space maintaining effect; the lower membrane layer can be well embedded with the tooth defect area through the shaping of the custom mold, so that the barrier membrane is prevented from shifting, no chemical cross-linking agent is generated, no inflammatory reaction is generated, and the application prospect is good.

Description

Barrier membrane capable of promoting alveolar bone regeneration and preparation method thereof
Technical Field
The invention relates to the field of bioremediation materials, in particular to a barrier membrane capable of promoting alveolar bone regeneration and a preparation method thereof.
Background
With the continuous development and maturation of the oral implant technology, the problem of tooth loss repair has been successfully solved. However, insufficient alveolar bone mass following tooth loss is a limitation and challenge in oral implant technology. To solve this problem, guided bone regeneration techniques have been developed. The guided bone regeneration technology is to use a barrier membrane to form a space in the missing region of teeth for the growth and proliferation of osteoprogenitor cells, thereby increasing the bone mass of alveolar bone to satisfy the later dental implantation.
Currently, there are a number of clinical barrier membrane types, which are classified into histocompatibility-incompatibilities and histocompatibility-incompatibilities, depending on whether they are histocompatible or not. The materials which are not compatible with tissues are polytetrafluoroethylene film materials and titanium film materials, and the materials have good mechanical properties and good space maintenance, so the materials become good news of dental growers at one time, 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 operation, and secondary infection risks are brought to patients. Thus, materials compatible with tissue are presently preferred in the marketplace. The histocompatible material is gradually decomposed by enzymes in body fluid during the process of promoting growth of alveolar bone; the decomposed components are partly absorbed by the tissue and partly removed from the body with the body fluid.
The existing materials compatible with tissues mainly comprise polylactic acid materials and animal-derived collagen materials. However, polylactic acid materials can inhibit the growth of alveolar bone due to the strong acidity of the degradation product lactic acid, but the animal-derived collagen materials on the market at present have poor mechanical properties and rapid degradation period, and can not meet the requirement of the growth of the alveolar bone. In order to solve this problem, there is a report that degradation characteristics and mechanical properties of animal-derived materials are improved by adding a chemical crosslinking agent, but there is a problem that an inflammatory reaction is easily induced by a residual crosslinking agent because the chemical crosslinking agent is difficult to remove. In addition, the current barrier membrane is difficult to position when in use, the barrier membrane deflection can cause the loss of a bone grafting space and the leakage of bone grafting materials, and the expected bone grafting effect cannot be met, so that certain auxiliary measures are required to be adopted for positioning in clinical application, the use is more troublesome, and the degree of jogging with a tooth defect area cannot be ensured.
Disclosure of Invention
In view of the above-described problems, the present invention provides a barrier film for promoting regeneration of alveolar bone, which does not contain a chemical crosslinking agent and does not generate an inflammatory reaction, and a method for preparing the same; has good mechanical properties 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 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 membrane layer is formed by paving three layers of collagen membranes, and the lower membrane layer collagen is formed by compounding hydroxyapatite.
Preferably, the collagen membrane of the upper membrane layer and the collagen protein of the lower membrane layer are both made of type I animal-derived collagen tissue; wherein, the three collagen films of the upper film layer are prepared from the submucosa or pericardium of small intestine of pig or cattle; the collagen of the lower membrane layer is prepared from skin or tendon of pig or cattle.
Further preferably, the thickness of the upper membrane layer is 0.06-0.45 mm, and the thickness of the three layers of collagen membranes is 0.02-0.15 mm; the thickness of the lower film layer is 0.05-0.45 mm, and the lower film layer is a specific structure formed by a custom mold.
Preferably, the aforementioned barrier film capable of promoting regeneration of alveolar bone, wherein the lower film layer is formed by pouring the blended protein component A and nano hydroxyapatite component B into a customized mold for cold molding; the protein component A is formed by mixing collagen and acetic acid according to the ratio of 1:50-1:100; the nano hydroxyapatite component B is formed by mixing hydroxyapatite and polyethylene glycol according to a feed liquid ratio of 1:100-1:300.
Next, the present invention provides a method for preparing the aforementioned barrier film for promoting alveolar bone regeneration, comprising the steps of:
s1: preparing an upper film layer: washing, degreasing, deproteinizing and virus-removing the submucosa or pericardium of small intestine of pig or cattle, cutting into a certain size, spreading and overlapping 3 layers, dehydrating and drying to prepare an upper membrane layer for later use;
s2: preparing a lower film layer: preparing collagen extracted from skin or tendon of pig or cattle into protein component A, mixing with nano hydroxyapatite component B, pouring into a mould, performing cold forming, dehydrating, and drying to obtain lower membrane layer;
s3: crosslinking: and (3) placing the prepared upper membrane layer on the lower membrane layer, placing the upper membrane layer under 30-40 tons of pressure for combined pressing, and then placing the upper membrane layer in a cobalt 60 radiation source with the radiation dose of 15-30 kGy for radiation crosslinking for 30 min-3 h, so that the barrier membrane capable of promoting alveolar bone regeneration can be obtained.
As a preferred technical scheme, step S1 prepares an upper film layer:
the degreasing reagent is mixed liquid of isopropanol, normal hexane, chloroform and methanol; preferably, the mixed solution of chloroform and methanol is mixed in a volume ratio of 2-3:1-2, preferably 2:1 or 3:2; the operation method is that the submucosa or pericardium of small intestine of pig or cow is soaked in the degreasing agent for 10-36 h, preferably 18-32 h, more preferably 20-30 h, and most preferably 24 h.
The deproteinizing agent is hydrogen peroxide solution, sodium hypochlorite solution or sodium dodecyl sulfate solution; preferably sodium hypochlorite solution or sodium dodecyl sulfate solution; further preferred is sodium dodecyl 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%; the method comprises the steps of carrying out a first treatment on the surface of the The operation method is that the submucosa or pericardium of small intestine of pig or cow is placed in the decellularized reagent to be soaked for 3 to 16 hours, preferably 5 to 12 hours, more preferably 6 to 10 hours, and most preferably 8 hours.
The virus removing agent 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 0.5mol/L to 2mol/L, preferably 0.5mol/L to 1.5mol/L, more preferably 1mol/L to 1.5mol/L, and most preferably 1.5mol/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%, preferably 75%; the operation method is that the submucosa or pericardium of small intestine of pig or cow is soaked in the virus removing agent for 1-10 hours, preferably 2-8 hours, more preferably 4-6 hours, and most preferably 6 hours.
As a preferable technical scheme, the step S2 is to prepare a lower membrane layer, which comprises two links of collagen purification and hydroxyapatite compounding; the specific operation is as follows:
s2-1: purifying: cutting the skin or tendon of the pig or cow after washing into slices with the thickness of 1-3 mm, preferably 2mm; placing the mixture into 0.1 to 5 percent of acetic acid or hydrochloric acid solution; adding trypsin, pepsin or ficin, stirring for 6-36 h at 2-8 ℃ for enzymolysis; then filtering out particles by using a stainless steel mesh with 20-40 meshes, and adding 0.5-4 mol/L sodium hydroxide solution to separate out protein to obtain collagen for later use. The concentration of the acetic acid solution is preferably 0.5% -3%, more preferably 1% -2%, and most preferably 1.5%; the concentration of the hydrochloric acid solution is preferably 1% -3%, more preferably 1.5% -3%, and most preferably 2%; the enzymolysis is preferably carried out by adopting ficin, and the enzymolysis condition is preferably stirring for 24 hours at the temperature of 4 ℃; the concentration of the sodium hydroxide solution is preferably 2 to 3mol/L, more preferably 3mol/L.
S2-2: compounding: dissolving precipitated collagen in acetic acid with the ratio of feed liquid of 1:50-1:100 and stirring by adopting a stirrer at the rotation speed of 200 rpm-500 rpm for 2-4 hours to form a protein component A; nano hydroxyapatite is prepared according to the feed liquid ratio of 1:100-1: 300 is added into polyethylene glycol solution, stirred by a stirrer at the rotating speed of 100 rpm-400 rpm for 3 h-6 h to form nano hydroxyapatite component B; in order to enable the nano-hydroxyapatite to be more uniformly dispersed in the collagen liquid, the prepared nano-hydroxyapatite component B is added into the component A for 3 to 5 times, and is stirred and blended by a stirrer at the rotating speed of 200 to 500rpm for 4 to 6 hours; and after blending, pouring the mixture into a formulated mold for cold forming, and dehydrating and drying the mixture to obtain the lower film layer. The feed solution ratio of the collagen dissolved in the acetic acid is preferably 1:60-1:80, more preferably 1:70-1:80, and most preferably 1:75; the ratio of the feed solution of the nano hydroxyapatite in the polyethylene glycol is preferably 1:150-1:250, more preferably 1:180-1:220, and most preferably 1:200.
As the preferable technical scheme, the step S1 is used for preparing the upper membrane layer and the step S2 is used for preparing the lower membrane layer, and the dehydration and drying modes are vacuum freeze drying or ethanol gradient dehydration and drying; wherein the technological parameters of vacuum freeze drying are as follows: drying at-45-30 deg.c for 48-72 hr; gradient dehydration and drying of ethanol is as follows: 25% -100%.
The beneficial effects of the invention are as follows:
1) The barrier membrane adopts purified type I collagen, has low immunogenicity and does not generate an immunogenic reaction.
2) The barrier membrane is of a double-layer membrane structure, and the lower membrane layer collagen and hydroxyapatite are compounded to form a double-component structure, so that the barrier membrane is excellent in mechanical property and excellent in space maintaining effect; the membrane layer is a specific structure formed by a customized mold, can be well embedded with a tooth defect area, prevents the barrier membrane from shifting, and prevents the loss of a bone grafting space and the leakage of bone grafting materials.
3) The upper membrane layer of the barrier membrane is formed by paving three layers of collagen membranes, has soft texture, can better fit soft tissues and is compatible with the tissues, so that inflammation is avoided, and good repairing and wound surface repairing promoting effects are achieved.
4) After the upper membrane layer and the lower membrane layer of the barrier membrane are pressed, the barrier membrane is crosslinked together in a cobalt 60 radiation source, and a chemical crosslinking agent is not used, so that inflammatory reaction is further avoided.
Drawings
FIG. 1 is a finished view of a barrier membrane for promoting alveolar bone regeneration according to the present invention;
FIG. 2 shows the situation of the teeth of a patient after the teeth are removed in an application example of the present invention;
FIG. 3 is a view of a patient following implantation of a barrier membrane of the present invention in an embodiment of the present invention;
FIG. 4 shows a first post-operative review repair of a patient in an embodiment of the present invention;
fig. 5 shows a second post-operative review of the patient in an embodiment 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 clearly and completely described below with reference to the embodiments and the accompanying drawings.
Example 1
The present embodiment is a barrier film for promoting regeneration of alveolar bone, which has a double-layered film structure including an upper film layer of a single-component structure and a lower film layer of a double-component structure; the upper membrane layer is formed by paving three layers of collagen membranes, and the lower membrane layer collagen is formed by compounding hydroxyapatite. The collagen membrane of the upper membrane layer and the collagen protein of the lower membrane layer are both made of type I animal source collagen tissues; wherein, the three collagen films of the upper film layer are prepared from the submucosa of the small intestine of the pig; the collagen of the lower membrane layer is prepared from pigskin. The thickness of the upper film layer is about 0.1mm, and the thicknesses of the three layers of collagen films are all 0.04mm; the thickness of the lower film layer was 0.2mm, which is a specific structure shaped by a custom mold.
The preparation method of the barrier film specifically comprises the following steps:
s1: preparing an upper film layer: washing, degreasing, deproteinizing and virus-removing the submucosa or pericardium of small intestine of pig or cattle, cutting into a certain size, spreading and overlapping 3 layers, dehydrating and drying to obtain an upper membranous layer for later use. The degreasing agent is mixed solution of chloroform and methanol, and the volume ratio of the chloroform to the methanol is 2:1; the operation method is that the submucosa of the small intestine of the pig is soaked in the degreasing agent for 24 h. The deproteinizing agent is sodium dodecyl sulfate solution with mass fraction concentration of 1%; the operation method is that the small intestinal mucosa of the pig is placed in the deproteinizing agent for ultrasonic soaking for 8 hours. The virus-removing reagent is oxalic acid solution with the mass percentage concentration of 15%; the operation method is that the submucosa of the small intestine of the pig is placed in the virus removing reagent for soaking for 6 hours. The dehydration and drying adopts vacuum freeze drying, and the technological parameters are as follows: drying at-45 deg.c for 48 hr.
S2: preparing a lower film layer: preparing collagen extracted from skin or tendon of pig or cattle into protein component A, mixing with nano hydroxyapatite component B, pouring into a mould, performing cold forming, dehydrating, and drying to obtain lower membrane layer; the specific operation is as follows:
s2-1: purifying: cutting the cleaned pigskin into slices with the thickness of 2mm, putting the slices into a 2% hydrochloric acid solution, adding ficin, and stirring for 24 hours at the temperature of 4 ℃ for enzymolysis; then filtering out particles by using a 30-mesh stainless steel screen, and adding 3mol/L sodium hydroxide solution to separate out protein to obtain collagen for later use.
S2-2: compounding: dissolving precipitated collagen in acetic acid with the ratio of feed liquid being 1:75, stirring by adopting a stirrer at the rotating speed of 500rpm for 3 hours to form a protein component A; adding nano hydroxyapatite into polyethylene glycol solution according to a feed liquid ratio of 1:200, stirring by adopting a stirrer at a rotating speed of 300rpm for 5 hours to form a nano hydroxyapatite component B; in order to ensure that the nano-hydroxyapatite can be more uniformly dispersed in the collagen liquid, the prepared nano-hydroxyapatite component B is added into the component A for 3 to 5 times, and is stirred and blended by a stirrer at the rotating speed of 500rpm for 6 hours; and after blending, pouring the mixture into a formulated mold for cold forming, and dehydrating and drying the mixture to obtain the lower film layer. The dehydration and drying adopts vacuum freeze drying, and the technological parameters are as follows: drying at-45deg.C and 72.
S3: crosslinking: the prepared upper membrane layer is laminated on the lower membrane layer, and is subjected to combined pressing under 40 tons of pressure, and then is put into a cobalt 60 radiation source with the radiation dose of 25kGy for radiation crosslinking for 1h, so that the barrier membrane capable of promoting the regeneration of alveolar bones is obtained, as shown in figure 1.
Example 2
The embodiment also prepares a barrier membrane capable of promoting regeneration of alveolar bone, wherein the three layers of collagen membranes of the upper membrane layer of the barrier membrane are prepared by bovine pericardium, and the collagen of the lower membrane layer is prepared by bovine tendon. The thickness of the upper membrane layer is about 0.4mm, and the thicknesses of the three layers of collagen membranes are all 0.13mm; the thickness of the lower film layer is 0.45mm. The preparation method comprises the following steps:
s1: preparing an upper film layer: washing, degreasing, deproteinizing and virus-removing the submucosa or pericardium of small intestine of pig or cattle, cutting into a certain size, spreading and overlapping 3 layers, dehydrating and drying to obtain an upper membranous layer for later use. Wherein the degreasing reagent is mixed solution of chloroform and methanol, and the mixing volume ratio is 3:2; the operation method is that the bovine pericardium is placed in a degreasing agent for soaking for 32 hours. The deproteinizing agent is sodium hypochlorite solution with the mass fraction concentration of 1.5%; the operation method is that the bovine pericardium is placed in the deproteinizing agent for ultrasonic soaking for 12 hours. The virus-removing reagent is ethanol solution, and the volume fraction concentration of the virus-removing reagent is 75%; the operation method is that the bovine pericardium is placed in the virus-removing reagent for soaking for 8 hours. The dehydration and drying adopts vacuum freeze drying, and the technological parameters are as follows: drying at-45 deg.c for 60 hr.
S2: preparing a lower film layer: the collagen extracted from the skin or tendon of the pig or the cow is prepared into a component A, and is mixed with a nano hydroxyapatite component B, poured into a mould for cold forming, dehydrated and dried to prepare a lower membrane layer for standby. The method comprises the following steps:
s2-1: purifying: cutting the cleaned beef tendon into slices with the thickness of 1 mm; placing in 3% acetic acid solution; adding trypsin, stirring at 8deg.C for 32 hr, and performing enzymolysis; then filtering out particles by using a 20-mesh stainless steel screen, and adding 4mol/L sodium hydroxide solution to separate out protein to obtain collagen for later use.
S2-2: compounding: dissolving precipitated collagen in acetic acid with the ratio of 1:80, stirring by a stirrer at the rotation speed of 400rpm for 4 hours to form a protein component A; adding nano hydroxyapatite into polyethylene glycol solution according to a feed liquid ratio of 1:250, stirring by adopting a stirrer at a rotating speed of 300rpm for 5 hours to form a nano hydroxyapatite component B; then adding the nano hydroxyapatite component B into the component A for 3 to 5 times, adopting a stirrer to stir and blend, and stirring for 4 hours at the rotating speed of 500 rpm; and after blending, pouring the mixture into a formulated mold for cold forming, and dehydrating and drying the mixture to obtain the lower film layer. The dehydration and drying adopts vacuum freeze drying, and the technological parameters are as follows: drying at-45 deg.c for 70 hr.
S3: crosslinking: and (3) placing the prepared upper membrane layer on the lower membrane layer, placing the upper membrane layer under 30 tons of pressure for combined pressing, and then placing the upper membrane layer in a cobalt 60 radiation source with the radiation dose of 30kGy for radiation crosslinking for 30 minutes to obtain the barrier membrane capable of promoting the regeneration of alveolar bones.
Example 3
The embodiment also prepares a barrier membrane capable of promoting regeneration of alveolar bone, wherein the upper membrane layer of the barrier membrane is prepared from bovine pericardium, and the collagen of the lower membrane layer is prepared from pig skin. The thickness of the upper film layer is 0.21mm, and the thicknesses of the three layers of collagen films are respectively 0.07mm; the thickness of the lower film layer was 0.36mm. The preparation method comprises the following steps:
s1: preparing an upper film layer: washing, degreasing, deproteinizing and virus-removing the submucosa or pericardium of small intestine of pig or cattle, cutting into a certain size, spreading and overlapping 3 layers, dehydrating and drying to obtain an upper membranous layer for later use. The degreasing reagent is a mixed solution of isopropanol and methanol, and the mixing volume ratio of the degreasing reagent and the mixed solution is 3:1; the operation method is that the bovine pericardium is placed in the degreasing agent for soaking for 18 hours. The deproteinizing agent is hydrogen peroxide solution, and the mass fraction concentration of the deproteinizing agent is 20%; the operation method is that the pericardium of the cattle is placed in the deproteinizing agent for ultrasonic soaking for 10 hours. The virus-removing reagent is sodium hydroxide solution, and the concentration of the virus-removing reagent is 1.5mol/L; the operation method is that the pericardium of the cattle is soaked in the virus-removing reagent for 10 hours. The dehydration and drying adopts ethanol gradient dehydration and drying, and the gradient of the dehydration and drying is as follows: 25% -100%.
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 mould for cold forming, dehydrating and drying to prepare a lower membrane layer for later use; the specific operation is as follows:
s2-1: purifying: cutting the cleaned pigskin into slices with the thickness of 3mm, and placing the slices into a 2% hydrochloric acid solution; adding pepsin, stirring at 8deg.C for 18 hr, and performing enzymolysis; then filtering out particles by using a 40-mesh stainless steel screen, and adding 2mol/L sodium hydroxide solution to separate out protein to obtain collagen for later use.
S2-2: compounding: dissolving precipitated collagen in acetic acid with the ratio of feed liquid being 1:100, stirring by adopting a stirrer at the rotating speed of 500rpm for 2 hours to form a protein component A; nano hydroxyapatite is prepared according to a feed liquid ratio of 1:300 is added into polyethylene glycol solution, and is stirred by a stirrer at the rotating speed of 400rpm for 3 hours to form nano hydroxyapatite component B; adding the nano hydroxyapatite component B into the component A for 3-5 times, adopting a stirrer to stir and blend, and stirring for 4 hours at 500 rpm; and after blending, pouring the mixture into a formulated mold for cold forming, and dehydrating and drying the mixture to obtain the lower film layer. The dehydration and drying adopts ethanol gradient dehydration and drying, and the gradient of the dehydration and drying is as follows: 25% -100%.
S3: crosslinking: and (3) placing the prepared upper membrane layer on the lower membrane layer, placing the upper membrane layer under 30 tons of pressure for combined pressing, and then placing the upper membrane layer into a cobalt 60 radiation source with the radiation dose of 15kGy for radiation crosslinking for 3 hours 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 film prepared in example 1. After the teeth of the patient are extracted and the dental sockets are filled, the barrier film prepared in the embodiment is used for covering the dental socket wounds and suturing; the gingival repair situation is reviewed on time basis, and the results are shown in fig. 2 to 5.
With time as the axis, fig. 1 and 2 are the same day of operation, and after the tooth extraction of the patient, the barrier film prepared in example 1 was sutured after filling the missing tooth, the lower film layer of the barrier film was molded by a specific mold, and the suture was performed by straddling the wound of the tooth socket. In the figure, it can be seen that the gum of the patient has edema after operation.
FIG. 3 shows the first review of the patient one week after the operation, and shows that the suture line of the teeth of the patient is in place, the gingiva is not red and swelling, and the incision is well healed; the disconnecting operation is performed on the same day.
Fig. 4 shows a second review of the patient two weeks after surgery, and it can be seen from the figure that the gingival mucosa is completely healed and the next tooth implantation preparation can be started.
The application example shows that the barrier membrane product can be well compatible with tissues, does not cause inflammation, can promote the growth and repair of alveolar bone and the healing of gingiva, and is beneficial to the later dental implant treatment. This is because the barrier membrane of the present invention employs purified type i collagen, which is less immunogenic and does not produce an immunogenic response; the membrane layer is of a specific structure formed by a customized mold, can be well embedded with a tooth defect area, prevents the barrier membrane from shifting, and prevents the loss of a bone grafting space and the leakage of bone grafting materials; the three-layer collagen film of the upper film layer has soft texture, can better fit soft tissues and be compatible with the tissues, avoids causing inflammation, and plays a good role in repairing and promoting wound surface repair; after the upper membrane layer and the lower membrane layer of the barrier membrane are pressed, the barrier membrane 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 membrane has 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 characteristics thereof. Accordingly, the embodiments are to be considered in all respects as illustrative and not restrictive. Furthermore, it should be understood that, although the present disclosure describes embodiments, this description is not intended to include only one embodiment, and those skilled in the art should understand that the present disclosure is not limited to the embodiments described herein, and that the embodiments described in the examples may be combined appropriately to form other embodiments that will be understood by those skilled in the art.

Claims (7)

1. A barrier membrane for promoting alveolar bone regeneration, characterized in that:
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 membrane layer is formed by paving three layers of collagen membranes,
the lower membrane layer is formed by compounding collagen and hydroxyapatite;
the thickness of the upper membrane layer is 0.06-0.45 mm, and the thicknesses of the three layers of collagen membranes are 0.02-0.15 mm;
the thickness of the lower film layer is 0.05-0.5 mm, and the lower film layer is formed by a custom mold;
the lower membrane layer is formed by pouring the blended protein component A and nano hydroxyapatite component B into a customized mold for freezing;
the protein component A is formed by mixing collagen and acetic acid according to the ratio of 1:50-1:100;
the nano hydroxyapatite component B is formed by mixing hydroxyapatite and polyethylene glycol according to a feed liquid ratio of 1:100-1:300;
the preparation process of the barrier film comprises the following steps:
firstly, cleaning, degreasing, deproteinizing and virus-removing the submucosa or pericardium of small intestine of a pig or a cow, cutting into a certain size, laying and overlapping 3 layers, dehydrating and drying to prepare an upper membrane layer;
then preparing collagen extracted from skin or tendon of pig or cattle into protein component A, mixing with nano hydroxyapatite component B, pouring into a mould for cold forming, dehydrating and drying to obtain lower membrane layer;
and then placing the prepared upper membrane layer on the lower membrane layer, placing the upper membrane layer under 30-40 tons of pressure for combined pressing, and then placing the upper membrane layer into a cobalt 60 radiation source with the radiation dose of 15-30 kGy for radiation crosslinking for 30 min-3 h, thus obtaining the barrier membrane capable of promoting alveolar bone regeneration.
2. The barrier membrane for promoting alveolar bone regeneration according to claim 1, wherein:
the collagen membrane of the upper membrane layer and the collagen protein of the lower membrane layer are both made of type I animal source collagen tissues; wherein,
the three-layer collagen membrane of the upper membrane layer is prepared from a small intestine submucosa or pericardium of a pig or a cow;
the collagen of the lower membrane layer is prepared from skin or tendon of pig or cattle.
3. A method for producing a barrier film for promoting alveolar bone regeneration according to claim 1 or 2, characterized by: the method comprises the following steps:
s1: preparing an upper film layer: washing, degreasing, deproteinizing and virus-removing the submucosa or pericardium of small intestine of pig or cattle, cutting into a certain size, spreading and overlapping 3 layers, dehydrating and drying to prepare an upper membrane layer for later use;
s2: preparing a lower film layer: preparing collagen extracted from skin or tendon of pig or cattle into protein component A, mixing with nano hydroxyapatite component B, pouring into a mould, performing cold forming, dehydrating, and drying to obtain lower membrane layer; the preparation of the lower membrane layer comprises two links of collagen purification and hydroxyapatite compounding; the specific operation is as follows:
s2-1: purifying: cutting the skin or tendon of the pig or cow after cleaning 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 h at the temperature of 2-8 ℃; then filtering out particles by using a stainless steel mesh with 20-40 meshes, and adding 0.5-4 mol/L sodium hydroxide solution to separate out protein to obtain collagen for later use;
s2-2: compounding: dissolving precipitated collagen in acetic acid with the ratio of feed liquid of 1:50-1:100 and stirring by adopting a stirrer at the rotation speed of 200 rpm-500 rpm for 2-4 hours to form a protein component A;
nano hydroxyapatite is prepared according to the feed liquid ratio of 1:100-1: 300 is added into polyethylene glycol solution, stirred by a stirrer at the rotating speed of 100 rpm-400 rpm for 3 h-6 h to form nano hydroxyapatite component B;
adding the nano hydroxyapatite component B into the component A for 3 to 5 times, adopting a stirrer to stir and blend, and stirring for 4 to 6 hours at the rotating speed of 200 to 500 rpm; after blending, pouring the mixture into a formulated mold for cold forming, and dehydrating and drying the mixture to obtain a lower film layer;
s3: crosslinking: and (3) placing the prepared upper membrane layer on the lower membrane layer, placing the upper membrane layer under 30-40 tons of pressure for combined pressing, and then placing the upper membrane layer in a cobalt 60 radiation source with the radiation dose of 15-30 kGy for radiation crosslinking for 30 min-3 h, so that the barrier membrane capable of promoting alveolar bone regeneration can be obtained.
4. The method for producing an alveolar bone regeneration promoting barrier membrane according to claim 3, wherein: step S1, preparing an upper film layer, wherein degreasing agent is mixed liquid of isopropanol, normal hexane, trichloromethane and methanol; the volume ratio of the chloroform to the methanol is 2-3: 1 to 2; the operation method is that the submucosa or pericardium of the small intestine of the pig or the cow is soaked in the degreasing agent for 10 to 36 hours.
5. The method for producing an alveolar bone regeneration promoting barrier membrane according to claim 3, wherein: step S1, preparing an upper film layer, wherein the deproteinizing agent is hydrogen peroxide solution, sodium hypochlorite solution or sodium dodecyl 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 is that the small intestine submucosa or pericardium of the pig or the cow is placed in the cell removing reagent for ultrasonic soaking for 3 to 16 hours.
6. The method for producing an alveolar bone regeneration promoting barrier membrane according to claim 3, wherein: step S1, preparing an upper film layer, wherein the virus-removing reagent is sodium hydroxide solution, oxalic acid solution or ethanol solution; the concentration of the sodium hydroxide solution is 0.5 mol/L-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 is that the small intestine submucosa or pericardium of the pig or the cow is soaked in the agent for removing the internal toxin for 1 to 10 hours.
7. The method for producing an alveolar bone regeneration promoting barrier membrane according to claim 3, wherein: step S1, preparing an upper membrane layer and step S2, preparing a lower membrane layer, and dehydrating and drying in a vacuum freeze drying or ethanol gradient dehydration and drying mode; wherein the technological parameters of vacuum freeze drying are as follows: drying at-45-30 deg.c for 48-72 hr; gradient dehydration and drying of ethanol is as follows: 25% -100%.
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