CN116474169A - Hydrogel surface modified biological bone calcium apatite particle material with blood clot regulating function and preparation method thereof - Google Patents
Hydrogel surface modified biological bone calcium apatite particle material with blood clot regulating function and preparation method thereof Download PDFInfo
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- CN116474169A CN116474169A CN202310323628.4A CN202310323628A CN116474169A CN 116474169 A CN116474169 A CN 116474169A CN 202310323628 A CN202310323628 A CN 202310323628A CN 116474169 A CN116474169 A CN 116474169A
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- 210000000988 bone and bone Anatomy 0.000 title claims abstract description 141
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 229910052586 apatite Inorganic materials 0.000 title claims abstract description 76
- 239000011575 calcium Substances 0.000 title claims abstract description 76
- 229910052791 calcium Inorganic materials 0.000 title claims abstract description 76
- 239000002245 particle Substances 0.000 title claims abstract description 76
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[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 VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 title claims abstract description 76
- 239000000017 hydrogel Substances 0.000 title claims abstract description 63
- 208000007536 Thrombosis Diseases 0.000 title claims abstract description 47
- 239000000463 material Substances 0.000 title claims abstract description 39
- 230000001105 regulatory effect Effects 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims description 16
- 230000001276 controlling effect Effects 0.000 claims abstract description 15
- 238000013329 compounding Methods 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims description 23
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 22
- 229920002674 hyaluronan Polymers 0.000 claims description 22
- 229960003160 hyaluronic acid Drugs 0.000 claims description 22
- 239000011159 matrix material Substances 0.000 claims description 15
- -1 aldehyde compounds Chemical class 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 14
- 239000003431 cross linking reagent Substances 0.000 claims description 9
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 7
- 239000004593 Epoxy Substances 0.000 claims description 7
- 150000001718 carbodiimides Chemical class 0.000 claims description 7
- 238000004132 cross linking Methods 0.000 claims description 7
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
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- 230000005847 immunogenicity Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
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- 239000000661 sodium alginate Substances 0.000 claims description 3
- AZKVWQKMDGGDSV-BCMRRPTOSA-N Genipin Chemical compound COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12 AZKVWQKMDGGDSV-BCMRRPTOSA-N 0.000 claims description 2
- 230000001413 cellular effect Effects 0.000 claims description 2
- AZKVWQKMDGGDSV-UHFFFAOYSA-N genipin Natural products COC(=O)C1=COC(O)C2C(CO)=CCC12 AZKVWQKMDGGDSV-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical group CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 abstract description 9
- 230000007547 defect Effects 0.000 abstract description 8
- 239000008280 blood Substances 0.000 abstract description 5
- 210000004369 blood Anatomy 0.000 abstract description 5
- 239000011664 nicotinic acid Substances 0.000 abstract description 5
- 230000006698 induction Effects 0.000 abstract description 4
- 230000003993 interaction Effects 0.000 abstract description 3
- 238000001035 drying Methods 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
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- 238000005520 cutting process Methods 0.000 description 10
- 229910021642 ultra pure water Inorganic materials 0.000 description 10
- 239000012498 ultrapure water Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 238000002791 soaking Methods 0.000 description 6
- 241000283690 Bos taurus Species 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 102000009123 Fibrin Human genes 0.000 description 5
- 108010073385 Fibrin Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 210000000845 cartilage Anatomy 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 229950003499 fibrin Drugs 0.000 description 5
- 238000010304 firing Methods 0.000 description 5
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- 239000000203 mixture Substances 0.000 description 5
- 239000005416 organic matter Substances 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- 238000005245 sintering Methods 0.000 description 5
- 210000004872 soft tissue Anatomy 0.000 description 5
- 238000002156 mixing Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 239000000316 bone substitute Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000017423 tissue regeneration Effects 0.000 description 3
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 2
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000004931 aggregating effect Effects 0.000 description 2
- 239000003114 blood coagulation factor Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 2
- 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 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000010478 bone regeneration Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940045110 chitosan Drugs 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- 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
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular 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
- 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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- 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
- 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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- 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
- A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61L2420/00—Materials or methods for coatings medical devices
- A61L2420/02—Methods for coating medical devices
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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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention provides a hydrogel surface modified biological bone calcium apatite particle material with a blood clot structure regulating function, which is formed by compounding biological bone calcium apatite particles with acellular matrixes and hydrogel with the blood clot structure regulating function. According to the invention, the hydrogel with the function of regulating and controlling the blood clot structure is introduced into the surface of the biological bone calcium apatite particles to prepare the modified biological bone calcium apatite particle material with the function of regulating and controlling the blood clot structure on the surface of the hydrogel, so that the original bionic three-dimensional porous structure of natural bone tissue is maintained, meanwhile, the problem of poor induction of fibrin structure during interaction with blood is solved, and the requirements of different bone defect areas are matched, thus the biological bone calcium apatite particle material has a wide application prospect.
Description
Technical Field
The invention relates to a hydrogel surface modified biological bone calcium apatite bone particle material with a blood clot regulating function and a preparation method thereof.
Background
Bone tumor, trauma, congenital development defect, widespread periodontal disease, alveolar bone absorption after missing teeth and the like all cause jawbone defect, and since the bone quantity around the defect part is insufficient, the implant cannot be used for repairing treatment, so that the application of bone substitute materials for regenerating and repairing jawbone defect becomes a preferred scheme.
The bone substitute material guiding bone tissue regeneration operation is a common means for solving the problem of jawbone defect, and a plurality of bone substitute materials are applied to clinic on the market at present, so that the requirement of clinically guiding bone tissue regeneration is met to a certain extent. The biological bone calcium apatite particle material has physical and chemical properties similar to those of bone tissue, and has three-dimensional structure of natural bone tissue maintained, excellent bone guiding effect and wide application. However, after the existing biological bone calcium apatite particle material is implanted into a body, a fibrin network with a bad structure can be formed after blood and the surface of the biological bone calcium apatite particle material are interacted, so that immune cell dysfunction such as local macrophages and the like is caused, and further, the local immune microenvironment is caused, and bone tissue regeneration mediated by the biological bone calcium apatite particle material is interfered.
The Chinese patent No. 103387646B discloses a preparation method of hydroxyapatite hydrogel for bone regeneration, which takes the hydrogel as a main body, and the hydroxyapatite particles are dissolved in a preset hydrogel liquid for polymerization, so that the natural bionic three-dimensional structure of the protozoon bone calcium apatite particle material is destroyed, and the three-dimensional structure is an important foundation for bone guidance.
In summary, how to improve the biological bone calcium apatite particle material, not only can keep the natural bionic three-dimensional structure, but also can have the capability of inducing the fibrin network structure in the blood clot, so that the biological bone calcium apatite particle material is suitable for organisms and becomes a technical problem which is difficult to overcome.
Disclosure of Invention
The invention aims to solve the technical problems that the existing biological bone calcium apatite particle material has poor interaction with blood and forms a fibrin network with poor structure. The hydrogel such as hyaluronic acid, chitosan and sodium alginate has the capability of changing blood clot structures and affecting blood clot functions by adsorbing coagulation factors, aggregating and activating platelets, interacting with fibrinogen, regulating and controlling the thickness and arrangement of blood clot fibrin and the like. Therefore, the invention provides a preparation method of a hydrogel surface modified biological bone calcium apatite particle material with a blood clot regulating function, which is characterized in that hydrogel with a blood clot regulating structure function is compounded on the surface of biological bone calcium apatite particles of a decellularized matrix, so that the original bionic three-dimensional porous structure of natural bone tissue is reserved, and meanwhile, the problem of poor induction of fibrin structure during interaction with blood is solved.
In order to solve the technical problems, the invention adopts the following technical scheme:
a hydrogel surface modified biological bone calcium apatite particle material with blood clot structure regulating function is formed by compounding calcium apatite particles with acellular matrix and hydrogel with blood clot structure regulating function.
Preferably, the acellular matrix calcium apatite particles are formed by removing the cellular matrix from natural bone, and only calcium apatite is contained, so that the immunogenicity of the natural bone is removed.
Preferably, it has the porous structure of natural cancellous bone.
The preparation method of the hydrogel surface modified biological bone calcium apatite particle material for regulating and controlling the blood clot structure function is characterized by comprising the following steps:
step one, preparing acellular matrix calcium apatite particles;
step two, preparing hydrogel preset liquid with the function of regulating and controlling blood clot structure;
step three: adding the biological bone calcium apatite particles prepared in the first step into the hydrogel preset liquid, and crosslinking under proper conditions;
step four: the hydrogel surface modified biological bone calcium apatite bone particle material with the function of regulating and controlling blood clot structure is prepared and collected for standby.
Preferably, the decellularized matrix calcium apatite particles may be formed from bone production of a variety of organisms.
Preferably, the hydrogel preset liquid with the function of regulating blood clot structure comprises hyaluronic acid and/or sodium alginate and chitosan which are crosslinked with a crosslinking agent, wherein the crosslinking agent is one or more of epoxy compounds, aldehyde compounds, sulfone compounds, carbodiimide, hydrazide compounds, disulfide and genipin.
Compared with the prior art, the invention has the beneficial effects that:
aiming at the problem that the traditional biological bone calcium apatite particles have poor induction of fibrin structures in blood clots, the hydrogel coating with the function of regulating and controlling the blood clots is introduced to the surfaces of the traditional biological bone calcium apatite particles to prepare the hydrogel surface modified biological bone calcium apatite bone particle material, so that the original bionic three-dimensional structure of natural bone tissues is reserved, the problem that the fibrin structures in the blood clots are poor in induction when blood interacts with the surfaces of the natural bone tissues is improved after the natural bone tissues are implanted into a body, the local bone immune microenvironment is improved, and the bone defect regeneration treatment effect of the biological bone calcium apatite particles is improved.
The biological bone calcium apatite particles with the hydrogel coating modification can be obtained by soaking the biological bone calcium apatite particles in the hydrogel preset liquid, and the preparation technology is simple, the cost is low, and the preparation method is suitable for mass production.
The hydrogel surface modified biological bone calcium apatite particles have good biological activity, no cytotoxicity and low immunogenicity, and have good application prospect. In addition, the hydrogel loaded on the particle surface can realize the loading of liposome or other nano drug carriers, and realize the accurate release and treatment of the drug at the bone defect position.
Drawings
The foregoing and/or additional aspects and advantages of the invention will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:
FIG. 1 is a schematic diagram showing the composite effect of hydrogel surface modified biological bone calcium apatite particles with blood clot regulating function;
FIG. 2 shows the macro morphology of hyaluronic acid hydrogel surface modified biological bone calcium apatite particles with different concentrations and blood clot regulating and controlling functions in the blood clot structure;
FIG. 3 shows the surface microscopic morphology of hyaluronic acid hydrogel modified biological bone calcium apatite particles with different concentrations and blood clot regulating and controlling functions in the invention.
Detailed Description
The detailed description is important to fully disclose, understand and reproduce the invention, as well as support and explain the claims. The description of the embodiments should be consistent with the technical solution adopted to solve the technical problem, and for a simple technical solution, only one example may be given, and for a technical solution with a wider protection scope, more than one example should be given to support the scope of protection claimed.
Embodiment one:
the preparation method of the hydrogel surface modified biological bone calcium apatite bone particle material with the blood clot regulating function comprises the following steps:
step one, preparing biological bone calcium apatite particles of acellular matrix: collecting heterogeneous biological bone, including but not limited to bovine bone, pig bone, etc., removing soft tissue and cartilage of bone surface with scissors, soaking in 10% -30% hydrogen peroxide and absolute ethyl alcohol for 24 hr, washing with ultrapure water, drying in a 60 deg.c drying oven, and removing organic matter from animal bone. Cutting the bone block into a required shape by using a linear cutting system, then placing the cut bone block into a muffle furnace for sintering to 400-1000 ℃, firing for 2-6 h, washing with ultrapure water, placing into a 60 ℃ drying oven for drying, grinding and screening by using a screen to obtain biological bone calcium apatite particles with the diameter of 0.25-1 mm.
Step two, preparing 0.1% -2% of hydrogel preset liquid: weighing 10mg of hyaluronic acid, adding 1ml of aqueous solution containing 1% (w/w) sodium hydroxide for dissolution, adding 4mM of cross-linking agent including but not limited to epoxy compounds, aldehyde compounds, sulfone compounds, carbodiimide, hydrazide compounds, disulfide, and uniformly mixing to obtain hyaluronic acid hydrogel preset liquid.
And thirdly, adding biological bone calcium apatite particles with the diameter of 0.25-1mm into a micropore mould, adding hyaluronic acid hydrogel preset liquid into the micropore mould, and crosslinking for 24 hours at 37 ℃.
And fourthly, placing the mixture into a drying oven for drying to obtain the surface modified biological bone calcium apatite bone particle material.
Embodiment two:
the preparation method of the hydrogel surface modified biological bone calcium apatite bone particle material with the blood clot regulating function comprises the following steps:
step one, preparing biological bone calcium apatite particles of acellular matrix: collecting heterogeneous biological bone, including but not limited to bovine bone, pig bone, etc., removing soft tissue and cartilage of bone surface with scissors, soaking in 10% -30% hydrogen peroxide and absolute ethyl alcohol for 24 hr, washing with ultrapure water, drying in a 60 deg.c drying oven, and removing organic matter from animal bone. Cutting the bone block into a required shape by using a linear cutting system, then placing the cut bone block into a muffle furnace for sintering to 400-1000 ℃, firing for 2-6 h, washing with ultrapure water, placing into a 60 ℃ drying oven for drying, grinding and screening by using a screen to obtain biological bone calcium apatite particles with the diameter of 0.25-1 mm.
Step two, preparing 2% -5% of hydrogel preset liquid: weighing 50mg of hyaluronic acid, adding 1ml of aqueous solution containing 1% (w/w) sodium hydroxide for dissolution, adding 4mM of cross-linking agent including but not limited to epoxy compounds, aldehyde compounds, sulfone compounds, carbodiimide and hydrazide compounds, disulfide, and uniformly mixing to obtain hyaluronic acid hydrogel preset liquid.
And thirdly, adding biological bone calcium apatite particles with the diameter of 0.25-1mm into a micropore mould, adding hyaluronic acid hydrogel preset liquid into the micropore mould, and crosslinking for 24 hours at 37 ℃.
And fourthly, placing the mixture into a drying oven for drying to obtain the surface modified biological bone calcium apatite bone particle material.
Embodiment III:
the preparation method of the hydrogel surface modified biological bone calcium apatite bone particle material with the blood clot regulating function comprises the following steps:
step one, preparing biological bone calcium apatite particles of acellular matrix: collecting heterogeneous biological bone, including but not limited to bovine bone, pig bone, etc., removing soft tissue and cartilage of bone surface with scissors, soaking in 10% -30% hydrogen peroxide and absolute ethyl alcohol for 24 hr, washing with ultrapure water, drying in a 60 deg.c drying oven, and removing organic matter from animal bone. Cutting the bone block into a required shape by using a linear cutting system, then placing the cut bone block into a muffle furnace for sintering to 400-1000 ℃, firing for 2-6 h, washing with ultrapure water, placing into a 60 ℃ drying oven for drying, grinding and screening by using a screen to obtain biological bone calcium apatite particles with the diameter of 0.25-1 mm.
Step two, preparing 5% -10% of hydrogel preset liquid: weighing 100mg of hyaluronic acid, adding 1ml of aqueous solution containing 1% (w/w) sodium hydroxide for dissolution, adding 4mM of cross-linking agent including but not limited to epoxy compounds, aldehyde compounds, sulfone compounds, carbodiimide, hydrazide compounds, disulfide, and uniformly mixing to obtain hyaluronic acid hydrogel preset liquid.
And thirdly, adding biological bone calcium apatite particles with the diameter of 0.25-1mm into a micropore mould, adding hyaluronic acid hydrogel preset liquid into the micropore mould, and crosslinking for 24 hours at 37 ℃.
And fourthly, placing the mixture into a drying oven for drying to obtain the surface modified biological bone calcium apatite bone particle material.
Embodiment four:
the preparation method of the hydrogel surface modified biological bone calcium apatite bone particle material with the blood clot regulating function comprises the following steps:
step one, preparing biological bone calcium apatite particles of acellular matrix: collecting heterogeneous biological bone, including but not limited to bovine bone, pig bone, etc., removing soft tissue and cartilage of bone surface with scissors, soaking in 10% -30% hydrogen peroxide and absolute ethyl alcohol for 24 hr, washing with ultrapure water, drying in a 60 deg.c drying oven, and removing organic matter from animal bone. Cutting the bone block into a required shape by using a linear cutting system, then placing the cut bone block into a muffle furnace for sintering to 400-1000 ℃, firing for 2-6 h, washing with ultrapure water, placing into a 60 ℃ drying oven for drying, grinding and screening by using a screen to obtain biological bone calcium apatite particles with the diameter of 0.25-1 mm.
Step two, preparing 10% -15% of hydrogel preset liquid: weighing 150mg of hyaluronic acid, adding 1ml of aqueous solution containing 1% (w/w) sodium hydroxide for dissolution, adding 4mM of cross-linking agent including but not limited to epoxy compounds, aldehyde compounds, sulfone compounds, carbodiimide and hydrazide compounds, disulfide, and uniformly mixing to obtain hyaluronic acid hydrogel preset liquid.
And thirdly, adding biological bone calcium apatite particles with the diameter of 0.25-1mm into a micropore mould, adding hyaluronic acid hydrogel preset liquid into the micropore mould, and crosslinking for 24 hours at 37 ℃.
And fourthly, placing the mixture into a drying oven for drying to obtain the surface modified biological bone calcium apatite bone particle material.
Fifth embodiment:
the preparation method of the hydrogel surface modified biological bone calcium apatite bone particle material with the blood clot regulating function comprises the following steps:
step one, preparing biological bone calcium apatite particles of acellular matrix: collecting heterogeneous biological bone, including but not limited to bovine bone, pig bone, etc., removing soft tissue and cartilage of bone surface with scissors, soaking in 10% -30% hydrogen peroxide and absolute ethyl alcohol for 24 hr, washing with ultrapure water, drying in a 60 deg.c drying oven, and removing organic matter from animal bone. Cutting the bone block into a required shape by using a linear cutting system, then placing the cut bone block into a muffle furnace for sintering to 400-1000 ℃, firing for 2-6 h, washing with ultrapure water, placing into a 60 ℃ drying oven for drying, grinding and screening by using a screen to obtain biological bone calcium apatite particles with the diameter of 0.25-1 mm.
Step two, preparing 15% -20% of hydrogel preset liquid: 200mg of hyaluronic acid is weighed, added into 1ml of aqueous solution containing 1% (w/w) sodium hydroxide for dissolution, and added with 4mM of cross-linking agent, including but not limited to epoxy compounds, aldehyde compounds, sulfone compounds, carbodiimide, hydrazide compounds, disulfide, and uniformly mixed to obtain hyaluronic acid hydrogel preset liquid.
And thirdly, adding biological bone calcium apatite particles with the diameter of 0.25-1mm into a micropore mould, adding hyaluronic acid hydrogel preset liquid into the micropore mould, and crosslinking for 24 hours at 37 ℃.
And fourthly, placing the mixture into a drying oven for drying to obtain the surface modified biological bone calcium apatite bone particle material.
In accordance with the preparation method of example 1, 10mg of hyaluronic acid was replaced with 0mg, 1mg, 5mg, 10mg, 15mg, respectively, i.e., 0mg/ml (i.e., PHA), 1mg/ml, 5mg/ml, 10mg/ml, 15mg/ml in the corresponding map. Fig. 2 shows the macroscopic morphology of hyaluronic acid hydrogel surface-modified biological bone calcium apatite particles with different concentrations and blood clot function for regulating and controlling blood clot structure.
The hydrogel in the embodiment can change the blood clot structure and influence the function of the blood clot by adsorbing coagulation factors, aggregating and activating platelets, and interacting with fibrinogen to regulate and control the thickness, the arrangement and the like of fibrin of the blood clot; the hydrogel with the function of regulating blood clots has stable physical shape, stable chemical property, good controllable mechanical strength, controllable biodegradation rate, no toxicity and no harm and good biocompatibility.
Claims (6)
1. The hydrogel surface modified biological bone calcium apatite particle material with the function of regulating and controlling blood clot structure is characterized by being formed by compounding calcium apatite particles with acellular matrixes and hydrogel with the function of regulating and controlling blood clot structure.
2. The hydrogel surface-modified biological bone calcium apatite particle material with the function of regulating blood clot structure according to claim 1, wherein the acellular matrix calcium apatite particles are formed by removing the cellular matrix from natural bone, only calcium apatite is contained, and the immunogenicity of the natural bone is removed.
3. The hydrogel surface-modified biological bone calcium apatite particle material with the function of regulating blood clot structure according to claim 1, which is characterized by a porous structure of natural cancellous bone.
4. The preparation method of the hydrogel surface modified biological bone calcium apatite particle material for regulating and controlling the blood clot structure function as set forth in claim 1, which is characterized by comprising the following steps:
step one, preparing acellular matrix calcium apatite particles;
step two, preparing hydrogel preset liquid with the function of regulating and controlling blood clot structure;
step three: adding the biological bone calcium apatite particles prepared in the first step into the hydrogel preset liquid, and crosslinking under proper conditions;
step four: the hydrogel surface modified biological bone calcium apatite bone particle material with the function of regulating and controlling blood clot structure is prepared and collected for standby.
5. The method for preparing a hydrogel surface-modified biological bone calcium apatite particle material with blood clot control function according to claim 4, wherein the acellular matrix calcium apatite particles can be formed by bone production of various organisms.
6. The preparation method of the hydrogel surface modified biological bone calcium apatite particle material with the blood clot regulating function according to claim 4, wherein the hydrogel preset liquid with the blood clot regulating structure is hyaluronic acid and/or sodium alginate and chitosan which are crosslinked with a crosslinking agent, and the crosslinking agent is one or more of epoxy compounds, aldehyde compounds, sulfone compounds, carbodiimide, hydrazide compounds, disulfide and genipin.
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