CN116920172A - Collagen fiber-biological ceramic composite artificial bone and preparation method thereof - Google Patents
Collagen fiber-biological ceramic composite artificial bone and preparation method thereof Download PDFInfo
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- 102000008186 Collagen Human genes 0.000 title claims abstract description 196
- 108010035532 Collagen Proteins 0.000 title claims abstract description 196
- 229920001436 collagen Polymers 0.000 title claims abstract description 196
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- 239000002131 composite material Substances 0.000 title claims abstract description 36
- 239000000919 ceramic Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000000463 material Substances 0.000 claims abstract description 28
- 239000000243 solution Substances 0.000 claims description 106
- 239000000835 fiber Substances 0.000 claims description 85
- 239000003462 bioceramic Substances 0.000 claims description 49
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000000843 powder Substances 0.000 claims description 21
- 239000005457 ice water Substances 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 17
- 241000283690 Bos taurus Species 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 12
- 238000004108 freeze drying Methods 0.000 claims description 11
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 10
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- 230000007935 neutral effect Effects 0.000 claims description 8
- 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 8
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- 238000002156 mixing Methods 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 7
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- 210000001361 achilles tendon Anatomy 0.000 claims description 6
- 230000000975 bioactive effect Effects 0.000 claims description 6
- 230000002500 effect on skin Effects 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 239000012475 sodium chloride buffer Substances 0.000 claims description 6
- 235000014653 Carica parviflora Nutrition 0.000 claims description 5
- 241000243321 Cnidaria Species 0.000 claims description 5
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- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 5
- 239000001506 calcium phosphate Substances 0.000 claims description 5
- 239000000378 calcium silicate Substances 0.000 claims description 5
- 229910052918 calcium silicate Inorganic materials 0.000 claims description 5
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 claims description 5
- FGZBFIYFJUAETR-UHFFFAOYSA-N calcium;magnesium;silicate Chemical compound [Mg+2].[Ca+2].[O-][Si]([O-])([O-])[O-] FGZBFIYFJUAETR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- 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 5
- 239000013049 sediment Substances 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 5
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 5
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 241000251468 Actinopterygii Species 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 239000007853 buffer solution Substances 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 235000010755 mineral Nutrition 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
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- 230000002138 osteoinductive effect Effects 0.000 abstract description 4
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 7
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- A—HUMAN NECESSITIES
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- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
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- A—HUMAN NECESSITIES
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/10—Ceramics or glasses
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- A—HUMAN NECESSITIES
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- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/12—Phosphorus-containing materials, e.g. apatite
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- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
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- A—HUMAN NECESSITIES
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
- A61L27/3645—Connective tissue
- A61L27/365—Bones
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
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Abstract
The invention relates to a collagen fiber-biological ceramic composite artificial bone, a preparation method and application thereof. The artificial bone has excellent bioactivity, osteoinductive property, degradability, shapeability and bone regeneration capability. The high porosity and the three-dimensional communicated porous structure are beneficial to the migration and transmission of osteoblasts and nutrient substances, promote the formation of new bones, and are replaced by the new bones along with gradual degradation and absorption of the artificial bones. The composite artificial bone has the advantages of low cost, wide raw material sources, high material utilization rate, simple preparation process and the like, and can be widely applied to clinical application.
Description
Technical Field
The invention relates to the technical field of biomedical materials and implantable medical devices, in particular to a collagen fiber-biological ceramic composite artificial bone and a preparation method thereof.
Background
Bone defects and bone damage problems have increased in recent years, mainly caused by diseases, wounds, aging, and the like. With the advent of aging population society, these situations have received more attention. Therefore, there is a need to develop an ideal artificial bone repair material clinically to more effectively treat these conditions. In addition, there is a strong need for artificial bones in the fields of medical cosmetology and orthopedics. In view of this situation, there is a need to develop safer and more effective artificial bone repair materials to meet the needs of the medical industry and patients.
Autologous bone and allogenic bone are the mainstream bone grafting materials widely used for treating skeletal defects, but their use is limited by the risk of resource shortages, immune rejection and disease infection. In recent years, development of artificial bone repair materials has been attracting attention. Platelet Rich Plasma (PRP) and stem cell therapy are novel bone substitute products, have high biological activity separated from human blood and bone marrow, but have individual differences and safety disputes in curative effect, and have difficulty in obtaining a large number of stem cells, long treatment period and high cost, so that the application and popularization of the novel bone substitute products are limited. The biological ceramic artificial bone has high bioactivity and excellent performance in bone defect filling, implant bracket and other aspects, but the defects of high cost, poor plasticity, brittleness and the like limit the application of the biological ceramic artificial bone in the field of bone repair. In contrast, the bioactive collagen sponge has similar components as human soft tissues, has good biocompatibility and bioactivity, is favorable for promoting the growth and repair of autologous bone tissues, and is also widely applied to artificial bone repair materials. However, the material has poor mechanical property and high degradation speed, and needs further scientific research and a great deal of practical experience to solve.
The collagen-based material is a common bone repair material, and has wide prospects, because collagen has the advantages of biocompatibility, biodegradability, promotion of formation of new cells, no potential virus hazard, processability and the like. In order to solve the problem of poor mechanical properties of collagen, the method for obtaining collagen fibers by a self-assembly method is an effective means for improving the properties of the collagen fibers. The invention innovatively combines the collagen fiber and the biological ceramic to prepare the collagen fiber composite artificial bone with mechanical property and osteoinductive activity. The collagen fiber artificial bone has simple preparation process, excellent biocompatibility and proper biodegradation period, excellent mechanical property and osteoinductive property, and is a safe and low-cost material which is very matched with the application requirement of bone repair. Therefore, the collagen fiber-biological ceramic composite artificial bone has excellent performance, can solve some defects existing in the traditional bone repair materials, and is expected to become the main stream of the bone repair materials.
Disclosure of Invention
In order to achieve the above object, the embodiment of the invention provides a collagen fiber-bioceramic composite artificial bone, which not only has excellent biocompatibility and osteoinductive repair capability, but also has excellent mechanical properties.
The present invention provides in a first aspect a method of preparing a collagen fiber material, the method comprising the steps of:
(1) Placing 0.0001-0.1. 0.1g/mL collagen in acidic solution, stirring at 4deg.C for several hours to make it fully absorb water and swell;
(2) Adding an alkaline solution into ice water bath to adjust the collagen solution to be neutral, then adding a phosphate/sodium chloride buffer solution, and adjusting the pH to about 7.4;
(3) The homogenate was incubated at 37℃and self-assembled for more than 12 hours. Then centrifugally separating the mixture to obtain a lower sediment, namely a collagen fiber initial product;
(4) And placing the collagen fibers in a suction filtration device, washing with deionized water, and removing excessive water to obtain the collagen fibers.
In a second aspect, the present invention provides a collagen fibre material obtainable by the process according to the first aspect of the present invention.
The invention provides in a third aspect the use of the collagen fiber material according to the second aspect of the invention for the preparation of collagen fiber-bioceramic composite artificial bones.
In a fourth aspect, the present invention provides a method of preparing a collagen fiber-bioceramic composite artificial bone, the method comprising the steps of:
(1) Adding the bioceramics into the collagen fibers, fully scattering, and uniformly mixing to obtain a collagen fiber-bioceramics mixture;
(2) Precooling the collagen fiber-biological ceramic mixture at-80 ℃ to-10 ℃, and freeze-drying in a freeze-drying device to obtain the collagen fiber-biological ceramic composite artificial bone.
The present invention also provides in a fifth aspect a method of preparing a collagen fiber-bioceramic composite artificial bone, the method comprising the steps of:
(1) Placing 0.0001-0.1. 0.1g/mL collagen in acidic solution, stirring at 4deg.C for several hours to make it fully absorb water and swell;
(2) Adding an alkaline solution into ice water bath to adjust the collagen solution to be neutral, then adding a phosphate/sodium chloride buffer solution, and adjusting the pH to about 7.4;
(3) The homogenate was incubated at 37℃and self-assembled for more than 12 hours. Then centrifugally separating the mixture to obtain a lower sediment, namely a collagen fiber initial product;
(4) Placing the collagen fibers in a suction filtration device, washing with deionized water and removing excessive water to obtain the collagen fibers;
(5) Adding the bioceramics into the collagen fibers, fully scattering, and uniformly mixing to obtain a collagen fiber-bioceramics mixture;
(6) Precooling the collagen fiber-biological ceramic mixture at-80 ℃ to-10 ℃, and freeze-drying in a freeze-drying device to obtain the collagen fiber-biological ceramic composite artificial bone.
In a sixth aspect, the present invention provides a collagen fiber-bioceramic composite artificial bone made according to the method of the fourth or fifth aspect of the present invention.
The invention provides in a seventh aspect the use of a collagen fiber-bioceramic composite artificial bone according to the sixth aspect of the invention in the manufacture of a bone implant.
The advantages of the invention and its excellent properties and excellent technical application effects at least comprise the following points:
(1) The concentration of the collagen solution is 0.0001-0.1 g/mL, and the viscosity of the whole solution is more moderate under the collagen concentration in the range, so that the influence of the viscosity on the local ion concentration is not caused;
(2) The bioceramics can select at least one of tricalcium phosphate, hydroxyapatite, calcium silicate, calcium carbonate, calcium magnesium silicate, bioglass, calcined bovine bone, calcined pig bone, coral, shell and other inorganic bioactive mineral materials, can select proper bioceramics to provide support and help promote new bone growth according to the damage or destruction condition of bone tissues of patients, and can use different materials, particle sizes and shapes to adapt to different operation requirements according to requirements;
(3) The bioceramics with the particle size of 0.1 mu m-2mm are mixed with the collagen fiber solution, and bone meal with the particle size is easier to disperse in the collagen fiber solution system and has satisfactory mechanical strength;
(4) Precooling the collagen fiber-bioceramic mixture at-80 ℃ to-10 ℃ and freeze-drying to remove redundant solvents in the sample, provide proper porosity for the collagen fiber artificial bone and facilitate the bone growth at the filling position;
drawings
FIG. 1 is a diagram of a collagen fiber-bioceramic composite artificial bone sample according to an embodiment.
FIG. 2 is a diagram of a sample of a composite artificial bone of collagen fiber-bioceramic of example II.
FIG. 3 is a diagram of a sample of a three collagen fiber-bioceramic composite artificial bone according to an embodiment.
Fig. 4 is a diagram of a sample of a three collagen fiber-bioceramic composite artificial bone according to an embodiment.
Fig. 5 is a diagram of a sample of a three collagen fiber-bioceramic composite artificial bone according to an embodiment.
FIG. 6 is a diagram of a sample of a three collagen fiber-bioceramic composite artificial bone according to an embodiment.
Fig. 7 is an SEM image of a collagen fiber-bioceramic composite artificial bone sample according to example one.
Fig. 8 is an SEM image of a sample of a composite artificial bone of example two collagen fibers-bioceramics.
Fig. 9 is an SEM image of a sample of a composite artificial bone of the triple collagen fiber-bioceramic of the example.
FIG. 10 is a comparative graph showing the compression modulus measurement of an uncrosslinked sample (1) of example, a thermally crosslinked sample (2) and a sample (3) of collagen which was not scattered by a high-speed disperser when mixing with bone powder.
Description of the embodiments
As described above, the present invention provides in a first aspect a method of preparing a collagen fiber solution, the method comprising the steps of:
(1) Placing 0.0001-0.1. 0.1g/mL (e.g. 0.01 g/mL) collagen in acidic solution, stirring at 4deg.C for several hours (e.g. 4 h-5 h), and allowing it to fully absorb water for swelling;
(2) Adding an alkaline solution into ice water bath to adjust the collagen solution to be neutral, then adding a phosphate/sodium chloride buffer solution, and adjusting the pH to about 7.4;
(3) The homogenate was incubated at 37℃and self-assembled for more than 12 hours. Then centrifugally separating the mixture to obtain a lower sediment, namely a collagen fiber initial product;
(4) And placing the collagen fibers in a suction filtration device, washing with deionized water, and removing excessive water to obtain the collagen fibers.
In some preferred embodiments, in step (1) the collagen type I fibres have a diameter of 10nm-10 μm.
In some preferred embodiments, the collagen in step (1) refers to a material having a type I collagen content of 80% and above, and the source thereof may be porcine dermal collagen, porcine achilles tendon collagen, bovine dermal collagen, bovine achilles tendon collagen, fish collagen, or any combination thereof.
In some preferred embodiments, the acid solution in step (1) is selected from aqueous hydrochloric acid, aqueous nitric acid and aqueous acetic acid, preferably aqueous acetic acid.
In some preferred embodiments, the concentration of acid in the collagen solution in step (1) is from 0.01 to 0.5M (e.g., 0.05, 0.15, 0.25, or 0.35M).
In some preferred embodiments, the pH in step (2) is adjusted using aqueous sodium hydroxide, preferably at a concentration of 0.1M to 1.1M (e.g., 0.1, 0.6, or 1.1M).
In some preferred embodiments, the addition of the alkaline containing solution and buffer solution is performed with continuous agitation while slowly adding dropwise.
The present invention provides in a second aspect a collagen fibre solution obtainable by the process according to the first aspect of the invention.
In a third aspect, the invention provides the use of a collagen fiber solution prepared by the method according to the first aspect of the invention or according to the second aspect of the invention in the preparation of a collagen fiber-bioceramic composite artificial bone.
In a fourth aspect, the present invention provides a method of preparing a collagen fiber-bioceramic composite artificial bone, the method comprising the steps of:
(1) Adding bioceramics into collagen fibers (for example, the mass ratio of collagen: bone powder=1:5, 1:15 and 1:25), fully scattering, and uniformly mixing to obtain a collagen fiber-bioceramic mixture;
(2) Precooling the collagen fiber-bioceramic mixture at-80deg.C to-10deg.C (e.g., -20deg.C, -60deg.C, -80deg.C), and freeze-drying in a freeze-drying device;
(3) Sterilizing the freeze-dried product to obtain the collagen fiber-biological ceramic composite artificial bone.
In some preferred embodiments, the collagen fiber solution is prepared by the method of the first aspect of the invention.
In some preferred embodiments, in step (1) the bioceramics comprises at least one of the inorganic bioactive mineral materials tricalcium phosphate, hydroxyapatite, calcium silicate, calcium carbonate, calcium magnesium silicate, bioglass, calcined bovine bone, calcined porcine bone, coral, and shell.
In some preferred embodiments, in step (1) the bioceramics have a powder particle size of 0.1 μm-2mm. Preferably, the mass ratio of the collagen fiber to the bioceramics is 1, wherein the mass ratio is 10 mu m-1000 mu m: 1-1:50, preferably 1:3-1:20.
in some preferred embodiments, the pre-cooling temperature in step (3) is from-80 ℃ to-10 ℃, preferably from-60 ℃ to-20 ℃.
The present invention also provides in a fifth aspect a method of preparing a collagen fiber-bioceramic composite artificial bone, the method comprising the steps of:
(1) Placing 0.0001-0.01-g/mL collagen in acidic solution, stirring at 4deg.C for several hours to allow it to fully absorb water and swell;
(2) Adding an alkaline solution into ice water bath to adjust the collagen solution to be neutral, then adding a phosphate/sodium chloride buffer solution, and adjusting the pH to about 7.4;
(3) The homogenate was incubated at 37℃and self-assembled for more than 12 hours. Then centrifugally separating the mixture to obtain a lower sediment, namely a collagen fiber initial product;
(4) Placing the collagen fibers in a suction filtration device, washing with deionized water and removing excessive water to obtain the collagen fibers;
(5) Adding the bioceramics into the collagen fibers, fully scattering, and uniformly mixing to obtain a collagen fiber-bioceramics mixture;
(6) Precooling the collagen fiber-biological ceramic mixture at-80 ℃ to-10 ℃, and freeze-drying in a freeze-drying device to obtain the collagen fiber-biological ceramic composite artificial bone.
In some preferred embodiments, in step (1) the collagen type I fibres have a diameter of 10nm-10 μm.
In some preferred embodiments, the collagen in step (1) refers to a material having a type I collagen content of 80% and above, and the source thereof may be porcine dermal collagen, porcine achilles tendon collagen, bovine dermal collagen, bovine achilles tendon collagen, fish collagen, or any combination thereof.
In some preferred embodiments, the acid solution in step (1) is selected from aqueous hydrochloric acid, aqueous nitric acid and aqueous acetic acid, preferably aqueous acetic acid.
In some preferred embodiments, the concentration of the acid in the collagen solution in step (1) is from 0.01 to 0.5M.
In some preferred embodiments, the pH in step (2) is adjusted using an aqueous sodium hydroxide solution, preferably at a concentration of 0.1M to 1.1M.
In some preferred embodiments, the addition of the alkaline containing solution and buffer solution is performed with continuous agitation while slowly adding dropwise.
In some preferred embodiments, in step (1) the bioceramics comprises at least one of the inorganic bioactive mineral materials tricalcium phosphate, hydroxyapatite, calcium silicate, calcium carbonate, calcium magnesium silicate, bioglass, calcined bovine bone, calcined porcine bone, coral, and shell.
In some preferred embodiments, in step (1) the bioceramics have a powder particle size of 0.1 μm-2mm. Preferably, the mass ratio of the collagen fiber to the bioceramics is 1, wherein the mass ratio is 10 mu m-1000 mu m: 1-1:50, preferably 1:3-1:20.
in some preferred embodiments, the pre-cooling temperature in step (3) is from-80 ℃ to-10 ℃.
In a sixth aspect, the present invention provides a collagen fiber-bioceramic composite artificial bone made according to the method of the fourth or fifth aspect of the present invention.
The invention provides in a seventh aspect the use of a collagen fiber-bioceramic composite artificial bone according to the sixth aspect of the invention in the manufacture of a bone implant.
In the present invention, the present inventors have made improvements and achieved corresponding technical effects in at least the following respects:
(1) The bioceramic is selected from at least one of inorganic bioactive mineral materials such as tricalcium phosphate, hydroxyapatite, calcium silicate, calcium carbonate, calcium magnesium silicate, bioglass, calcined Os bovis Seu Bubali, calcined Os Sus Domestica, coral, and shell. Preferably, the bioactive glass 45S5, beta-TCP, calcined bovine bone, calcined porcine bone, 45S5 and the like are harmless to human bodies, have good affinity with bone tissues, can be firmly combined with surrounding bone tissues, are beneficial to improving the strength of materials, reducing the difference between the materials and the bone tissues, and improving the bone guiding property and the inducibility of the materials;
(2) The collagen type I is adopted, and self-assembled into the collagen fiber with a triple helix structure in the solution, so that each performance of the composite material is optimized, and the three-dimensional network structure of the collagen fiber can promote the growth of new bones and is gradually replaced by real bone tissues; type I collagen is an important protein constituting connective tissue of human body, has high elasticity and stretching ability, is mainly present in human tissues such as skin, bone, muscle, blood vessels, etc., and plays a vital role in maintaining normal physiological functions of these tissues. The type I collagen is generally used for repairing bone defects in the medical field, can replace and strengthen the functions of natural bones, can reduce operation time and recovery period, and has less rejection reaction risk;
(3) The concentration of the collagen solution is 0.0001 to 0.1g/ml, and under the range, the viscosity of the whole solution is more moderate, so that the self-assembly of the collagen solution into the collagen fiber solution is facilitated, and the influence caused by overlarge or overlarge local ion concentration due to overlarge or overlarge local ion concentration is avoided;
(4) The bioceramics with the particle size of 0.1 mu m-2mm are mixed with the collagen fiber solution, and bone meal with the mesh number is easier to disperse in a polymer solution system and has satisfactory mechanical strength;
(5) The swelling of the collagen under the good solvent is carried out at 4 ℃, and because the good solvent of the collagen is adopted, the swelling can be completed under low temperature, thereby avoiding the damage to the activity of the collagen and reducing the risks of volatilization, toxicity and the like of the solvent under higher temperature;
(6) The composite material is precooled at low temperature and then freeze-dried, so that a certain porosity is provided for the material, and residual impurities in the material are removed.
Examples
The present invention will be illustrated by way of examples below, but the scope of the invention should not be construed as being limited to these examples.
Embodiment one:
(1) A 0.1% strength collagen solution was prepared using deionized water and swelled at 36 h at 4 ℃;
(2) After full swelling, uniformly dispersing by a high-speed disperser under the condition of ice water bath;
(3) Placing the uniformly dispersed 0.1% collagen solution in an ice-water bath, adding sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate, and adjusting the pH value of the solution to be neutral; placing the collagen solution in a water bath kettle at 37 ℃ for incubation, self-assembling for 48 hours, wherein the upper layer is a collagen fiber primary product after 48 hours;
(4) Centrifuging the collagen fiber solution in a centrifuge to obtain a collagen fiber solution, and calculating dry weight of the collagen fiber according to a certain proportion, wherein the dry weight of the collagen fiber solution is 1:15 calculating to obtain the quality of beta-TCP, wherein the grain size of the bone meal is 150-500 mu m;
(5) Adding bone powder into collagen fiber solution, stirring with high-speed disperser, freezing 48 h, and lyophilizing 72 h;
(6) And carrying out vacuum thermal crosslinking on the obtained product in a vacuum oven for 24 h to obtain the product.
The average compressive modulus and standard deviation of the collagen fiber-bioceramic composite artificial bone obtained in the different ways in example one are shown in the following table, wherein the uncrosslinked sample is designated 1, the thermally crosslinked sample is designated 2, and the sample which was not scattered by a high-speed disperser when mixing collagen with bone powder is designated 3.
| Sample of | 1 | 2 | 3 |
| Average compression modulus/MPa | 1.2069 | 0.67316 | 0.21089 |
| Standard deviation of | 0.1576 | 0.27148 | 0.10312 |
Embodiment two:
(1) A 1% strength collagen solution was prepared using 0.05M acetic acid solution and swelled 48 h at 4 ℃;
(2) After full swelling, uniformly dispersing by a high-speed disperser under the condition of ice water bath;
(3) Titrating the uniformly dispersed 1% collagen solution to neutrality by using 0.5M sodium hydroxide solution, then placing the collagen solution in an ice-water bath, adding sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate, and regulating the pH of the solution to neutrality; placing the collagen solution in a water bath kettle at 37 ℃ for incubation, self-assembling for 48 hours, wherein the upper layer is a collagen fiber primary product after 48 hours;
(4) Centrifuging the collagen fiber solution in a centrifuge to obtain a collagen fiber solution, and calculating dry weight of the collagen fiber according to a certain proportion, wherein the dry weight of the collagen fiber solution is 1:20, calculating to obtain 45S5 mass, wherein the grain size of the selected bone powder is 150-500 mu m;
(5) Adding bone powder into collagen fiber solution, stirring with high-speed disperser, freezing 48 h, and lyophilizing 72 h;
(6) And carrying out vacuum thermal crosslinking on the obtained product in a vacuum oven to obtain the product 36 h.
Embodiment III:
(1) A 5% strength collagen solution was prepared using deionized water and swelled 72 h at 4 ℃;
(2) After full swelling, uniformly dispersing by a high-speed disperser under the condition of ice water bath;
(3) Placing the evenly dispersed 5% collagen solution in an ice-water bath, adding sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate, and adjusting the pH value of the solution to be neutral; placing the collagen solution in a water bath kettle at 37 ℃ for incubation, and self-assembling for 72 hours, wherein the upper layer is a collagen fiber primary product;
(4) Centrifuging the collagen fiber solution in a centrifuge to obtain a collagen fiber solution, and calculating dry weight of the collagen fiber according to a certain proportion, wherein the dry weight of the collagen fiber solution is 1:5, calculating to obtain 45S5 mass, wherein the grain size of the selected bone powder is 500-1000 mu m;
(5) Adding bone powder into collagen fiber solution, stirring with high-speed disperser, freezing 72 h, and lyophilizing 96-h;
(6) And carrying out vacuum thermal crosslinking 48 h on the obtained product in a vacuum oven to obtain the product.
Embodiment four:
(1) A 3% strength collagen solution was prepared using deionized water and swelled 72 h at 4 ℃;
(2) After full swelling, uniformly dispersing by a high-speed disperser under the condition of ice water bath;
(3) Placing the evenly dispersed 3% collagen solution in an ice-water bath, adding sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate, and adjusting the pH value of the solution to be neutral; placing the collagen solution in a water bath kettle at 37 ℃ for incubation, self-assembling for 60 hours, wherein the upper layer is a collagen fiber primary product after 60 hours;
(4) Centrifuging the collagen fiber solution in a centrifuge to obtain a collagen fiber solution, and calculating dry weight of the collagen fiber according to a certain proportion, wherein the dry weight of the collagen fiber solution is 1:3, calculating to obtain the quality of the pig bone powder, wherein the grain size of the selected bone powder is 500-1000 mu m;
(5) Adding bone powder into collagen fiber solution, stirring with high-speed disperser, freezing 72 h, and lyophilizing 96-h;
(6) And carrying out vacuum thermal crosslinking on the obtained product in a vacuum oven to obtain the product 36 h.
Fifth embodiment:
(1) A 2% strength collagen solution was prepared using 0.1. 0.1M acetic acid solution and swelled 48 h at 4 ℃;
(2) After full swelling, uniformly dispersing by a high-speed disperser under the condition of ice water bath;
(3) Titrating the uniformly dispersed 2% collagen solution to neutrality by using 0.5M sodium hydroxide solution, then placing the collagen solution in an ice-water bath, adding sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate, and regulating the pH of the solution to neutrality; placing the collagen solution in a water bath kettle at 37 ℃ for incubation, self-assembling for 48 hours, wherein the upper layer is a collagen fiber primary product after 48 hours;
(4) Centrifuging the collagen fiber solution in a centrifuge to obtain a collagen fiber solution, and calculating dry weight of the collagen fiber according to a certain proportion, wherein the dry weight of the collagen fiber solution is 1:30, calculating to obtain the quality of beta-TCP, wherein the grain size of the bone meal is 150-500 mu m;
(5) Adding bone powder into collagen fiber solution, stirring with high-speed disperser, freezing 60 h, and lyophilizing 72 h;
(6) And carrying out vacuum thermal crosslinking on the obtained product in a vacuum oven for 12 h to obtain the product.
Example six:
(1) A 5% strength collagen solution was prepared using 0.25M acetic acid solution and swelled 48 h at 4 ℃;
(2) After full swelling, uniformly dispersing by a high-speed disperser under the condition of ice water bath;
(3) Titrating the uniformly dispersed 5% collagen solution to neutrality by using 0.5M sodium hydroxide solution, then placing the mixture in an ice-water bath, adding sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate, and adjusting the pH of the solution to neutrality; placing the collagen solution in a water bath kettle at 37 ℃ for incubation, and self-assembling for 72 hours, wherein the upper layer is a collagen fiber primary product;
(4) Centrifuging the collagen fiber solution in a centrifuge to obtain a collagen fiber solution, and calculating dry weight of the collagen fiber according to a certain proportion, wherein the dry weight of the collagen fiber solution is 1:15, calculating to obtain the quality of the bovine bone powder, wherein the grain size of the selected bone powder is 10-150 mu m;
(5) Adding bone powder into collagen fiber solution, stirring with high-speed disperser, freezing 48 h, and lyophilizing 72 h;
(6) And (5) carrying out vacuum thermal crosslinking on the obtained product in a vacuum oven to obtain the product 18 h.
Embodiment seven:
(1) A 0.1% strength collagen solution was prepared using 0.5. 0.5M acetic acid solution and swollen at 4 ℃ for 6 h;
(2) After full swelling, uniformly dispersing by a high-speed disperser under the condition of ice water bath;
(3) Titrating the uniformly dispersed 0.1% collagen solution to neutrality by using 0.5. 0.5M sodium hydroxide solution, then placing the collagen solution in an ice-water bath, adding sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate, and regulating the pH of the solution to neutrality; placing the collagen solution in a water bath kettle at 37 ℃ for incubation, and self-assembling for 12 hours, wherein the upper layer is a collagen fiber primary product;
(4) Centrifuging the collagen fiber solution in a centrifuge to obtain a collagen fiber solution, and calculating dry weight of the collagen fiber according to a certain proportion, wherein the dry weight of the collagen fiber solution is 1:5, calculating to obtain the quality of the bovine bone powder, wherein the grain size of the selected bone powder is 500-1000 mu m;
(5) Adding bone powder into collagen fiber solution, stirring with high-speed disperser, freezing 48 h, and lyophilizing 72 h;
(6) And carrying out vacuum thermal crosslinking on the obtained product in a vacuum oven for 12 h to obtain the product.
Claims (8)
1. The collagen fiber-bioceramic composite artificial bone is characterized by comprising collagen fibers and bioceramics and having a three-dimensional communicated porous structure. The preparation method comprises the following steps:
(1) Placing 0.0001-0.1. 0.1g/mL collagen in acidic solution, stirring at 4deg.C for several hours to make it fully absorb water and swell;
(2) Adding an alkaline solution into ice water bath to adjust the collagen solution to be neutral, then adding a phosphate/sodium chloride buffer solution, and adjusting the pH to about 7.4;
(3) The homogenate was incubated at 37℃and self-assembled for more than 12 hours. Then centrifugally separating the mixture to obtain a lower sediment, namely a collagen fiber initial product;
(4) Placing the collagen fibers in a suction filtration device, washing with deionized water and removing excessive water to obtain the collagen fibers;
(5) Adding the bioceramics into the collagen fibers, fully scattering, and uniformly mixing to obtain a collagen fiber-bioceramics mixture;
(6) Precooling the collagen fiber-biological ceramic mixture at-80 ℃ to-10 ℃, and freeze-drying in a freeze-drying device to obtain the composite artificial bone.
2. The collagen fibers according to claim 1, which are type I collagen fibers having a diameter of 10nm to 10 μm.
3. The bioceramic of claim 1, comprising at least one of tricalcium phosphate, hydroxyapatite, calcium silicate, calcium carbonate, calcium magnesium silicate, bioglass, calcined bovine bone, calcined porcine bone, coral, and shell inorganic bioactive mineral materials.
4. A bioceramic according to claims 1 and 3, having a powder particle size of 0.1 μm-2mm.
5. The method of claim 1, wherein the collagen is a material having a type I collagen content of 80% or more, and the source of the collagen is porcine dermal collagen, porcine achilles tendon collagen, bovine dermal collagen, bovine achilles tendon collagen, fish collagen, or any combination thereof.
6. The method of claim 1, wherein the acidic solution in step (1) is an aqueous acetic acid solution, an aqueous hydrochloric acid solution, or an aqueous nitric acid solution, or any combination thereof, and the acidic solution has a concentration of 0.01 to 0.5M.
7. The method of claim 1, wherein the alkaline solution in step (2) is sodium bicarbonate solution, sodium carbonate solution, sodium hydroxide solution, or any combination thereof, the alkaline solution having a concentration of 0.1M to 1.1M; the phosphate/sodium chloride buffer solution in step (2) is preferably Phosphate Buffer (PBS), and the concentration of the buffer solution is 0.1-10M.
8. A method according to claims 1, 3, characterized in that the mass ratio of collagen fibers to bioceramics is 1:1 to 1:50.
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