CN112402703A - Double-layer porous composite biological membrane containing bioactive mineral material and preparation method thereof - Google Patents
Double-layer porous composite biological membrane containing bioactive mineral material and preparation method thereof Download PDFInfo
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- 239000011148 porous material Substances 0.000 claims abstract description 5
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 7
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 229940036811 bone meal Drugs 0.000 claims description 2
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- ZOMBKNNSYQHRCA-UHFFFAOYSA-J calcium sulfate hemihydrate Chemical compound O.[Ca+2].[Ca+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O ZOMBKNNSYQHRCA-UHFFFAOYSA-J 0.000 claims description 2
- 238000009826 distribution Methods 0.000 claims description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 2
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 2
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract description 6
- 239000011780 sodium chloride Substances 0.000 abstract description 3
- 238000005185 salting out Methods 0.000 abstract description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 abstract description 2
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- 239000010410 layer Substances 0.000 description 69
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 18
- -1 phosphorus ions Chemical class 0.000 description 13
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- 230000004663 cell proliferation Effects 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
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- 108010035532 Collagen Proteins 0.000 description 2
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- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- 230000004071 biological effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
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- 238000001354 calcination Methods 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
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- 238000006243 chemical reaction Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
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- 229910001392 phosphorus oxide Inorganic materials 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- VSAISIQCTGDGPU-UHFFFAOYSA-N tetraphosphorus hexaoxide Chemical compound O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 description 1
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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
-
- 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
- A61L31/14—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
- A61L31/146—Porous materials, e.g. foams or sponges
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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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- 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
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- Heart & Thoracic Surgery (AREA)
- General Health & Medical Sciences (AREA)
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- Dispersion Chemistry (AREA)
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Abstract
The invention provides a double-layer porous composite biological membrane containing bioactive mineral materials and a preparation method thereof. The composite membrane includes: a first layer of film and a second layer of film adhered to a surface of the first layer of film; the first layer of film is composed of one or more film-forming materials of polylactic acid, PLGA, polylactic acid-caprolactone copolymer, polycaprolactone, polyvinyl alcohol, polyglycolic acid and silk fibroin, and the first layer of film is a compact layer; the second film is prepared from polylactic acid, PLGA, polylactic acid-caprolactone copolymer, polycaprolactone, polyvinyl alcohol and polyvinyl alcoholAcid, one or more film forming materials of silk fibroin SF and bioactive mineral materials, wherein the second film is a porous layer. The preparation method of the invention avoids NaCl and NaHCO3In the traditional solvent pouring/salting-out method as a pore-forming agent, the pore-forming agent is wrapped by a film-forming material, so that the pore-forming agent cannot be dissolved out, closed pores and Cl are formed‑Residue and the like.
Description
Technical Field
The invention belongs to the technical field of medical materials, and particularly relates to a double-layer porous composite biological membrane containing a bioactive mineral material and a preparation method thereof.
Background
Guided Bone Regeneration (GBR) refers to a therapeutic approach that utilizes the properties of barrier membranes to mechanically block fibrous connective tissue and surrounding soft tissue from entering bone defect sites and ensure that osteoblasts outside the bone surface have sufficient time to proliferate, thereby preventing regeneration and performing directional repair.
However, the single barrier membrane has limited capability of promoting the proliferation of osteoblasts, and is difficult to simultaneously meet various requirements of bone tissue repair, and the composite material can integrate the advantages of each single material, thereby improving the physical, chemical and biological properties of the barrier membrane and simultaneously being more easily meeting the requirements of bone tissue engineering.
Polylactic acid, polylactic-co-polyglycolic acid (PLGA), and other film-forming materials have good biocompatibility, have been widely used in the field of bioengineering, and have been approved by the FDA in the united states and officially included in the pharmacopoeia as pharmaceutical excipients.
The bioactive mineral material has good bioactivity and biocompatibility, is used as an induction factor for bone or tooth repair, and has a good effect of promoting cell proliferation. For example, bioactive silicon, bioactive glass, etc. can rapidly generate ion exchange when meeting water, and a hydroxyapatite layer similar to bone tissue components is formed on the surface through a series of reactions, so that stable chemical bonding is formed with bone tissues or soft tissues of a human body, a large amount of biomolecules (growth factors, collagen, etc.) are adsorbed, cell proliferation is promoted, and bone tissue regeneration is induced.
In the prior art, basically, a single composite stent, a composite membrane or a medical product is prepared by completely mixing film-forming materials such as polylactic acid and the like with bioactive glass powder, for example, in patent CN108721694A, polylactic acid-glycolic acid copolymer is dissolved in a solvent, then bioactive glass powder is added, and then a composite degradable bone nail is obtained by sintering, and the preparation method is too complex. And the adoption of a single composite membrane can not meet various requirements of bone tissue repair.
Disclosure of Invention
In view of the defects and shortcomings of the prior art, an object of the present invention is to provide a dual-layer porous composite biological membrane containing bioactive mineral materials, which can serve as a good physical barrier to selectively separate different tissues, and the porous structure provides sufficient growth space for cell adsorption and regeneration of new tissues, and can slowly release bioactive mineral materials in the degradation process to promote the generation of new tissues, thereby promoting the healing of soft tissues and hard tissues.
The invention also aims to provide a preparation method of the double-layer porous composite biological membrane containing the bioactive mineral material, which is simple and feasible and can prepare the composite biological membrane with excellent performance.
The technical scheme adopted by the invention for solving the technical problem is as follows:
a two-layer porous composite biofilm comprising a bioactive mineral material, the composite membrane comprising: a first layer of film and a second layer of film adhered to a surface of the first layer of film; the first layer of film is composed of one or more film-forming materials of polylactic acid, polylactic acid-glycolic acid copolymer (PLGA), polylactic acid-caprolactone copolymer, polycaprolactone, polyvinyl alcohol, polyglycolic acid and Silk Fibroin (SF), and the first layer of film is a compact layer; the second layer of film is composed of one or more film-forming materials of polylactic acid, polylactic-co-glycolic acid (PLGA), polylactic-co-caprolactone, polycaprolactone, polyvinyl alcohol, polyglycolic acid and Silk Fibroin (SF) and a bioactive mineral material, and is a porous layer.
In the above-mentioned double-layered porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, the double-layered porous composite biofilm is used in which the first layer membrane is adjacent to fibrous tissue and the second layer membrane is adjacent to bone tissue.
In the above-mentioned two-layer porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, the pore size distribution on the second membrane is 50 μm to 750 μm (e.g., 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm), and the porosity is 50% to 90% (e.g., 60%, 65%, 70%, 75%, 80%, 85%).
In the above-mentioned two-layer porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, the first layer of the membrane has a thickness of 0.5 to 2.5mm (e.g., 0.6mm, 0.8mm, 1.0mm, 1.5mm, 2.0 mm).
In the above-mentioned two-layer porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, the thickness of the second membrane is 0.5 to 3.5mm (e.g., 0.7mm, 0.9mm, 1.4 mm, 1.9mm, 2.4mm, 2.9mm, 3.3 mm).
In the above-mentioned two-layer porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, the bioactive mineral material is present in the second membrane at 0.1% to 50% by mass (e.g., 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%); preferably, the bioactive mineral material is present in the second layer of membrane at 1% to 40% by mass (e.g. 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%); more preferably, the bioactive mineral material is present in the second layer of the membrane at a mass percentage of 5% to 30% (e.g. 8%, 10%, 15%, 20%, 25%).
In the above-mentioned double-layer porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, the bioactive mineral material is any one or a mixture of several of bioactive silicon, bioactive glass, hydroxyapatite, calcium sulfate hemihydrate, tricalcium phosphate, autologous bone meal particles or DBM particles.
In the above-mentioned two-layer porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, the bioactive mineral material has a particle size of 1 nm to 150 μm.
In the above-mentioned two-layer porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, the bioactive silicon is an oxide comprising 40 to 70 wt% of silica and 30 to 60 wt% of an oxide selected from phosphorus, calcium and sodium; wherein the silicon dioxide forms a three-dimensional network structure, and calcium ions and phosphorus ions are orderly distributed among three-dimensional network silicon atoms; wherein the 5-valent silicon atom and/or the 6-valent silicon atom accounts for 1 mol% to 10 mol% of the total silicon atoms; the content of phosphorus oxide is 2-5 wt%. The content of the calcium oxide in the bioactive silicon is preferably 10 to 20 wt%. The content of the sodium oxide is preferably 10 to 20 wt%. The bioactive silicon of the present invention can be prepared according to the method described in the patent application with the publication number of CN106362214A, and the commercial Regesi regenerated silicon produced by Beijing Happy probiotic high and new technology company Limited can also be adopted, and the Regesi regenerated silicon of any type of the product can be used in the present invention. The material is made of SiO2、CaO、P2O5The formed Regesi regenerated silicon is solid powder, has huge specific surface area and stable pH after contacting body fluid. The bioactive silicon can also be a regenerated silicon material-POSS-based regenerated medical material prepared by the method disclosed in the Chinese patent publication No. CN109771692A, and the material is a product obtained by calcining polyhedral oligomeric silsesquioxane to remove organic components, so as to form a polyhedral cage-shaped structure consisting of Si-O-Si bonds in silicon oxide as a frame, and a novel bioactive material in which calcium and phosphorus elements are embedded. The bioactive silicon of the present invention can also be prepared according to the method described in patent application No. CN 110101904B.
A preparation method of the double-layer porous composite biological membrane containing the bioactive mineral material comprises the following steps:
1) dissolving a film forming material in a solvent, and forming a film in a grinding tool after the film forming material is fully dissolved to obtain a first layer film (a compact layer);
2) adding a bioactive mineral material into a solvent, uniformly mixing, adding a film-forming material, fully stirring and dissolving, and then uniformly mixing to obtain a mixed solution;
3) freeze-drying the mixed solution obtained in the step 2), removing residual solvent, and drying to obtain a second layer of membrane (porous layer);
4) wetting the surface of the first layer of membrane, then placing the second layer of membrane on the wetted surface of the first layer of membrane, and pressing to tightly combine the first layer of membrane and the second layer of membrane, thus obtaining the double-layer porous composite biological membrane.
In the above method for preparing a double-layer porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, in the steps 1) and 2), the solvent is one or a mixture of more of ethyl acetate, dichloromethane, acetone, N-methylpyrrolidone, chloroform, tetrahydrofuran, hexafluoroisopropanol, acetonitrile and dioxane.
In the above method for preparing a two-layer porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, in the step 2), the mixing is performed by ultrasonic oscillation, so that the bioactive mineral material and the solvent are uniformly mixed, and the bioactive mineral material, the solvent and the film-forming material are uniformly mixed.
In the above method for producing a two-layer porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, in the step 3), the mixed solution is pre-frozen before the freeze-drying, and then the freeze-drying is performed; preferably, the pre-freezing temperature is-30 ℃ to-10 ℃ (for example-25 ℃, 20 ℃ and 15 ℃) and the time is 1h to 3h (for example 1.5h, 2h and 2.5 h).
In the above-mentioned double-layered porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, in the step 3), the temperature of the freeze-drying is-65 ℃ to-35 ℃ (e.g., -60 ℃, -55 ℃, -50 ℃, -45 ℃, -40 ℃) and the time is 12h to 48h (e.g., 17h, 22h, 27h, 32h, 37h, 42 h). In the above-mentioned two-layer porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, in the step 3), the residual solvent is removed by soaking in absolute ethanol.
In the above-mentioned double-layered porous composite biofilm containing a bioactive mineral material, as a preferred embodiment, in the step 4), the surface of the first membrane is wetted by continuously introducing a solvent vapor to the surface of the first membrane, and preferably, the solvent is at least one of ethyl acetate, dichloromethane, acetone, N-methylpyrrolidone, chloroform, tetrahydrofuran, hexafluoroisopropanol, acetonitrile, and dioxane.
Compared with the prior art, the invention has the following positive effects:
(1) the composite membrane has a double-layer membrane structure, the first layer membrane is a compact layer, has a smooth surface and has a good cell blocking effect, and the second layer membrane is a porous structure, so that a sufficient growth space is provided for cell adsorption and regeneration of new tissues, and the combination of bone cells and the membrane is facilitated.
(2) The second layer of the composite membrane can slowly release bioactive mineral materials in the degradation process, the bioactive mineral materials and water generate ion exchange, a layer of hydroxyapatite is formed on the surface, and a large number of biomolecules (growth factors, collagen and the like) are adsorbed, so that soft tissue and hard tissue cells and intravascular tissue are guided to be attached to the composite membrane for growth, the proliferation of the cells is promoted, the regeneration of bone tissues is induced, and the repair of the hard tissue (bone) is promoted.
(3) In the preparation method of the invention, NaCl and NaHCO are avoided3In the traditional solvent pouring/salting-out method as a pore-forming agent, the pore-forming agent is wrapped by a film-forming material, so that the pore-forming agent cannot be dissolved out, closed pores and Cl are formed-Residue, etc., which affects the adhesion and growth of cells.
Drawings
FIG. 1 shows the results of the porosities of the two-layer porous composite biofilms obtained in examples 1, 2 and 3;
FIG. 2 is a result of cell proliferation rate test of the biofilms obtained in example 1 and comparative example 1.
Detailed Description
In order to highlight the objects, technical solutions and advantages of the present invention, the present invention is further illustrated by the following examples, which are presented by way of illustration of the present invention and are not intended to limit the present invention. The technical solution of the present invention is not limited to the specific embodiments listed below, and includes any combination of the specific embodiments.
The double-layer porous composite membrane prepared from the film-forming materials such as polylactic acid and the like and bioactive mineral materials can play a good physical barrier to selectively separate different tissues, is used in the fields of GBR (guided bone regeneration), GTR (guided tissue regeneration) and adhesion prevention, can fully play the advantage of the induction activity of the bioactive mineral materials, and stimulates the growth of histiocytes and angiogenesis tissues.
The preparation method of the invention adopts the vacuum freeze drying technology to prepare the porous structure containing the bioactive mineral material (wherein the solvent forms solidified particles after being frozen, and the solid state is directly volatilized into the gas state under the vacuum state, so that a gap is formed), thereby avoiding NaCl and NaHCO3In the traditional solvent pouring/salt leaching method used as a pore-forming agent, the pore-forming agent is wrapped by a film-forming material, so that the problems of incapability of dissolving out the pore-forming agent, closed pores, Cl & lt- & gt residue and the like are caused, and the adhesion and growth of cells are influenced; meanwhile, a dense structure is prepared by a solvent volatilization method, and then the two layers of membranes are compounded together to prepare the barrier membrane capable of promoting induced cell proliferation.
Example 1
1) Dissolving 3g of PLGA in 10ml of dioxane and 2ml of dichloromethane, fully dissolving, forming a film in a polytetrafluoroethylene grinding tool, and drying for 24 hours under natural conditions to obtain a first film (compact layer);
2) adding 0.3g of commercially available Regesi regenerated silicon (V type) produced by Beijing Happy probiotic high and new technology Limited into 10ml of dioxane and 2ml of dichloromethane, adding 3g of PLGA to fully stir and dissolve after uniform ultrasonic oscillation, and then performing ultrasonic oscillation for 10 min;
3) freezing the solution obtained in the step 2 in a polytetrafluoroethylene mold at-20 ℃ for 2h, then putting the polytetrafluoroethylene mold in a vacuum freeze dryer for freeze drying at-45 ℃ for 24h to obtain a porous structure, then soaking the porous structure in absolute ethyl alcohol, replacing the absolute ethyl alcohol every 3 hours to remove residual solvent, and finally putting the porous structure in a fume hood for drying at room temperature for 24h to obtain a second membrane (porous layer);
4) and continuously introducing dioxane steam to the surface of the first membrane for 10min, uniformly wetting, placing the second membrane on the surface of the wetted first membrane, slightly pressing to fully and tightly combine the two membranes, and drying at room temperature for 2h to obtain the double-layer porous composite biological membrane.
Example 2
1) Dissolving 3g of PLGA in 10ml of dioxane and 2ml of dichloromethane, fully dissolving, forming a film in a polytetrafluoroethylene grinding tool, and drying for 24 hours under natural conditions to obtain a first film (compact layer);
2) adding 0.6g of commercial Regesi regenerated silicon V produced by Beijing Happy probiotic high and new technology Limited into 10ml of dioxane and 2ml of dichloromethane, adding 3g of PLGA after uniform ultrasonic oscillation, fully stirring and dissolving, and then performing ultrasonic oscillation for 10 min;
3) freezing the solution obtained in the step 2 in a polytetrafluoroethylene mold at-20 ℃ for 2h, then putting the polytetrafluoroethylene mold in a vacuum freeze dryer for freeze drying at-45 ℃ for 24h to obtain a porous structure, then soaking the porous structure in absolute ethyl alcohol, replacing the absolute ethyl alcohol every 3 hours to remove residual solvent, and finally putting the porous structure in a fume hood for drying at room temperature for 24h to obtain a second membrane (porous layer);
4) and continuously introducing dioxane steam to the surface of the first membrane for 10min, uniformly wetting, placing the second membrane on the surface of the wetted first membrane, slightly pressing to fully and tightly combine the two membranes, and drying at room temperature for 2h to obtain the double-layer porous composite biological membrane.
Example 3
1) Dissolving 3g of PLGA in 10ml of dioxane and 2ml of dichloromethane, fully dissolving, forming a film in a polytetrafluoroethylene grinding tool, and drying for 24 hours under natural conditions to obtain a first film (compact layer);
2) adding 0.9g of commercial Regesi regenerated silicon V produced by Beijing Happy probiotic high and new technology Limited into 10ml of dioxane and 2ml of dichloromethane, adding 3g of PLGA after uniform ultrasonic oscillation, fully stirring and dissolving, and then performing ultrasonic oscillation for 10 min;
3) freezing the solution obtained in the step 2 in a polytetrafluoroethylene mold at-20 ℃ for 2h, then putting the polytetrafluoroethylene mold in a vacuum freeze dryer for freeze drying at-45 ℃ for 24h to obtain a porous structure, then soaking the porous structure in absolute ethyl alcohol, replacing the absolute ethyl alcohol every 3 hours to remove residual solvent, and finally putting the porous structure in a fume hood for drying at room temperature for 24h to obtain a second membrane (porous layer);
4) and continuously introducing dioxane steam to the surface of the first membrane for 10min, uniformly wetting, placing the second membrane on the surface of the wetted first membrane, slightly pressing to fully and tightly combine the two membranes, and drying at room temperature for 2h to obtain the double-layer porous composite biological membrane.
Comparative example 1
1) Dissolving 3g of PLGA in 10ml of dioxane and 2ml of dichloromethane, fully dissolving, forming a film in a polytetrafluoroethylene grinding tool, and drying for 24 hours under natural conditions to obtain a first film (compact layer);
2) adding 3g of PLGA into 10ml of dioxane and 2ml of dichloromethane, and fully stirring for dissolving;
3) freezing the solution obtained in the step 2 in a polytetrafluoroethylene mold at-20 ℃ for 2h, then putting the polytetrafluoroethylene mold in a vacuum freeze dryer for freeze drying at-45 ℃ for 24h to obtain a porous structure, then soaking the porous structure in absolute ethyl alcohol, replacing the absolute ethyl alcohol every 3 hours to remove residual solvent, and finally putting the porous structure in a fume hood for drying at room temperature for 24h to obtain a second membrane (porous layer);
4) and continuously introducing dioxane steam to the surface of the first membrane for 10min, uniformly wetting, placing the second membrane on the surface of the wetted first membrane, slightly pressing to fully and tightly combine the two membranes, and drying at room temperature for 2h to obtain the double-layer porous composite biological membrane.
Test example 1
Porosity: the porosity of the two-layer porous composite biological membrane obtained in the examples 1, 2 and 3 and the comparative example 1 is characterized, and the result is tested.
The porosity test is carried out by adopting a volume method, 6 samples are extracted from each group, and the average value is calculated according to the following formula:
porosity (%) - (V1-V3)/(V2-V3)
V1: initial volume of absolute ethanol in graduated cylinder
V2: volume of cylinder after adding material
V3: volume of residual absolute ethyl alcohol in measuring cylinder after material is taken out
The porosity results of the two-layer porous composite biological membranes obtained in the examples 1, 2 and 3 are shown in the attached drawing 1, and the two-layer porous composite biological membranes obtained in the examples 1, 2 and 3 have higher porosity, wherein the porosity of the example 1 is 86.8; example 2 had a porosity of 82.3; example 3 had a porosity of 74.2; the porosity of comparative example 1 was 76.2.
Test example 2
Cell proliferation assay: and (3) inoculating a proper amount of MG-63 cell suspension on the pre-wetted double-layer porous composite biological membrane of the example 1 and the comparative example 1 in a 24-well plate, taking out the membrane after 12 hours, 24 hours and 48 hours respectively, rinsing, transferring to a new 24-well plate, adding a proper amount of improved Martin culture medium and a detection kit, culturing at 37 ℃ for 3 hours, and testing the absorbance.
Cell proliferation rate (%) - (treatment group a value-negative control group a value)/(treatment group a value) × 100%
The test results of the biofilms obtained in example 1 and comparative example 1 are shown in fig. 2, and it can be seen from fig. 2 that the cell proliferation rates of the double-layer porous composite biofilm using the biofilm of example 1 in the application after 12h, 24h and 48h are respectively: 20.5, 28.5 and 37.6, and the cell proliferation rates of the double-layer porous composite biological membrane of the comparative example 1 are 20.4, 26.8 and 34.1 after 12, 24 and 48 hours respectively; compared with the double-layer porous composite biological membrane of the comparative example 1, the double-layer porous composite biological membrane of the embodiment 1 has a higher cell proliferation rate particularly after 24 and 48 hours of culture.
Claims (10)
1. A two-layer porous composite biofilm comprising a bioactive mineral material, said composite membrane comprising: a first layer of film and a second layer of film adhered to a surface of the first layer of film; the first film is composed of one or more film-forming materials of polylactic acid, polylactic acid-glycolic acid copolymer, polylactic acid-caprolactone copolymer, polycaprolactone, polyvinyl alcohol, polyglycolic acid and silk fibroin, and the first film is a compact layer; the second layer of film is composed of one or more film-forming materials of polylactic acid, polylactic acid-glycolic acid copolymer, polylactic acid-caprolactone copolymer, polycaprolactone, polyvinyl alcohol, polyglycolic acid and silk fibroin and bioactive mineral materials, and is a porous layer.
2. The bilayer porous composite biofilm containing bioactive mineral material of claim 1, wherein in use said bilayer porous composite biofilm has a first membrane in proximity to fibrous tissue and a second membrane in proximity to bone tissue.
3. The two-layer porous composite biofilm containing bioactive mineral material as claimed in claim 1, wherein the pore size distribution on the second layer of membrane is 50 μm to 750 μm and the porosity is 50% to 90%.
4. The two-layer porous composite biofilm containing bioactive mineral material of claim 1, wherein said first layer of membrane has a thickness of 0.5-2.5 mm; preferably, the thickness of the second layer of film is 0.5-3.5 mm;
preferably, the mass percentage of the bioactive mineral material in the second layer of the film is 0.1% -50%;
preferably, the mass percentage of the bioactive mineral material in the second layer of the film is 1% -40%; more preferably, the bioactive mineral material is 5-30% by mass of the second layer of membrane.
5. The double-layer porous composite biological membrane containing the bioactive mineral material according to claim 1, wherein the bioactive mineral material is any one or a mixture of several of bioactive silicon, bioactive glass, hydroxyapatite, calcium sulfate hemihydrate, tricalcium phosphate, autologous bone meal particles or DBM particles;
preferably, the bioactive mineral material has a particle size of from 1 nanometer to 150 microns.
6. A method of producing a two-layer porous composite biofilm containing bioactive mineral material as defined in any one of claims 1 to 5, comprising:
1) dissolving a film forming material in a solvent, and forming a film in a grinding tool after the film forming material is fully dissolved to obtain a first layer of film;
2) adding a bioactive mineral material into a solvent, uniformly mixing, adding a film-forming material, fully stirring and dissolving, and then uniformly mixing to obtain a mixed solution;
3) freeze-drying the mixed solution obtained in the step 2), removing residual solvent, and drying to obtain a second layer of membrane;
4) wetting the surface of the first layer of membrane, then placing the second layer of membrane on the wetted surface of the first layer of membrane, and pressing to tightly combine the first layer of membrane and the second layer of membrane, thus obtaining the double-layer porous composite biological membrane.
7. The method for preparing the double-layer porous composite biological membrane containing the bioactive mineral material according to claim 6, wherein in the steps 1) and 2), the solvent is one or a mixture of ethyl acetate, dichloromethane, acetone, N-methylpyrrolidone, trichloromethane, tetrahydrofuran, hexafluoroisopropanol, acetonitrile and dioxane.
8. The method according to claim 6, wherein the mixing in step 2) is performed by ultrasonic oscillation, so that the bioactive mineral material and the solvent are uniformly mixed, and the bioactive mineral material, the solvent and the film-forming material are uniformly mixed.
9. The method according to claim 6, wherein in step 3), the mixed solution is pre-frozen before the freeze-drying, and then the freeze-drying is performed;
preferably, the pre-freezing temperature is-30 ℃ to-10 ℃ and the time is 1h to 3 h.
Preferably, the temperature of the freeze drying is-65 ℃ to-35 ℃, and the time is 12h to 48 h.
10. The method for preparing a two-layer porous composite biofilm containing a bioactive mineral material as claimed in claim 6, wherein in the step 3), the residual solvent is removed by soaking in absolute ethyl alcohol;
preferably, in the step 4), the surface of the first film is wetted by continuously introducing solvent vapor to the surface of the first film, and preferably, the solvent is at least one of ethyl acetate, dichloromethane, acetone, N-methylpyrrolidone, chloroform, tetrahydrofuran, hexafluoroisopropanol, acetonitrile and dioxane.
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