CN100536935C - Composite porous calcium phosphate bone cement and method for making same - Google Patents
Composite porous calcium phosphate bone cement and method for making same Download PDFInfo
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- CN100536935C CN100536935C CNB2006101134653A CN200610113465A CN100536935C CN 100536935 C CN100536935 C CN 100536935C CN B2006101134653 A CNB2006101134653 A CN B2006101134653A CN 200610113465 A CN200610113465 A CN 200610113465A CN 100536935 C CN100536935 C CN 100536935C
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- 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 title claims abstract description 65
- 239000001506 calcium phosphate Substances 0.000 title claims description 63
- 239000002639 bone cement Substances 0.000 title claims description 53
- 229910000389 calcium phosphate Inorganic materials 0.000 title claims description 49
- 235000011010 calcium phosphates Nutrition 0.000 title claims description 49
- 239000002131 composite material Substances 0.000 title claims description 43
- 238000000034 method Methods 0.000 title claims description 8
- 229920000520 poly(3-hydroxybutyrate-co-3-hydroxyvalerate) Polymers 0.000 claims abstract description 51
- 239000000843 powder Substances 0.000 claims abstract description 47
- 239000007788 liquid Substances 0.000 claims abstract description 35
- 239000004568 cement Substances 0.000 claims abstract description 28
- 230000015556 catabolic process Effects 0.000 claims abstract description 22
- 238000006731 degradation reaction Methods 0.000 claims abstract description 22
- 239000007787 solid Substances 0.000 claims abstract description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical group [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 14
- 238000001035 drying Methods 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims description 78
- 239000004005 microsphere Substances 0.000 claims description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- 239000012890 simulated body fluid Substances 0.000 claims description 35
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 28
- 239000008367 deionised water Substances 0.000 claims description 25
- 229910021641 deionized water Inorganic materials 0.000 claims description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 24
- 238000007596 consolidation process Methods 0.000 claims description 21
- 239000012153 distilled water Substances 0.000 claims description 19
- 230000005855 radiation Effects 0.000 claims description 19
- 239000007790 solid phase Substances 0.000 claims description 18
- 238000007654 immersion Methods 0.000 claims description 15
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 14
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 14
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 14
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 238000004140 cleaning Methods 0.000 claims description 12
- 229920001577 copolymer Polymers 0.000 claims description 12
- 239000002002 slurry Substances 0.000 claims description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 12
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 10
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 239000007853 buffer solution Substances 0.000 claims description 9
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 8
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 8
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 8
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 239000008055 phosphate buffer solution Substances 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 6
- 230000008859 change Effects 0.000 claims description 6
- 239000011521 glass Substances 0.000 claims description 6
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 6
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 6
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 6
- 235000010413 sodium alginate Nutrition 0.000 claims description 6
- 239000000661 sodium alginate Substances 0.000 claims description 6
- 229940005550 sodium alginate Drugs 0.000 claims description 6
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000007983 Tris buffer Substances 0.000 claims description 5
- 238000000498 ball milling Methods 0.000 claims description 5
- 239000001110 calcium chloride Substances 0.000 claims description 5
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 5
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 5
- 239000001103 potassium chloride Substances 0.000 claims description 5
- 235000011164 potassium chloride Nutrition 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 5
- 235000011152 sodium sulphate Nutrition 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 4
- 235000019800 disodium phosphate Nutrition 0.000 claims description 4
- 239000004567 concrete Substances 0.000 claims description 3
- 239000000470 constituent Substances 0.000 claims description 3
- -1 distilled water compound Chemical class 0.000 claims description 3
- 239000011806 microball Substances 0.000 abstract description 7
- 230000008439 repair process Effects 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 229920000642 polymer Polymers 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
- 210000000988 bone and bone Anatomy 0.000 description 27
- 239000000463 material Substances 0.000 description 17
- 230000007547 defect Effects 0.000 description 11
- 238000001727 in vivo Methods 0.000 description 9
- 239000011159 matrix material Substances 0.000 description 7
- 229920001661 Chitosan Polymers 0.000 description 4
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 4
- 235000019700 dicalcium phosphate Nutrition 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 210000004409 osteocyte Anatomy 0.000 description 3
- 230000008467 tissue growth Effects 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000694 effects Effects 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
- 238000007711 solidification Methods 0.000 description 2
- 230000008023 solidification Effects 0.000 description 2
- GBNXLQPMFAUCOI-UHFFFAOYSA-H tetracalcium;oxygen(2-);diphosphate Chemical compound [O-2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GBNXLQPMFAUCOI-UHFFFAOYSA-H 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 208000035126 Facies Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000973495 Odax pullus Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001976 enzyme digestion Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000002188 osteogenic effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
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- Materials For Medical Uses (AREA)
Abstract
The invention relates to compound porous calcium orthophosphate skeleton cement. Wherein, said cement is formed by calcium orthophosphate skeleton cement powder, 3-hydroxy butanoic acid-CO-3-hydroxy pentanoic acid polymer microball, and solidify liquid. And the production comprises: preparing orthophosphate skeleton cement solid powder; preparing analogue humor; mixing the PHVV microball radiated by Co60 gama-ray; washing, drying and emerging it in the analogue humor, to be washed and dried; then mixing the PHBV microball and solid powder, to be added with solidify liquid to obtain the product. The invention has high strength, quick degradation and controllable degradation speed. And it can be used to repair skeleton hurt and used as skeleton support.
Description
Technical field
The invention belongs to the calcium phosphate cement composite material technical field, but calcium phosphate cement composite material of particularly a kind of compound vivo degradation pore-forming and preparation method thereof.
Background technology
The self-curable calcium phosphate bone cement has that under room temperature or Human Physiology ambient temperature in-situ solidifying, firming body structure and composition are similar with composition to natural bone mineral facies structure, in the operation arbitrarily plastotype, can fill characteristics such as the bone of different shape is damaged, can be widely used in fracture fixation, bone defect repair, tooth section and clinical scopes such as decorative sursery reparation and pharmaceutical carrier, be the focus of bone reparation and hard tissue substituting material area research.
Though common calcium phosphate bone cement material also has certain porosity, but because the hole yardstick is nanoscale or submicron order, lack the macropore that impels the osseous tissue growth, not only osteocyte can not be grown into, tissue fluid also is difficult to infiltrate, and this material degraded and absorbed process is in vivo successively carried out, thereby absorbance is low, degraded has slowly hindered the generation and the reconstruction of new bone tissue.Tang Peifu adds sodium bicarbonate in the consolidation liquid of carbonating hydroxyapatite bone cement, preparation porous bone cement material, big porosity in the firming body more than 70 microns can reach 40%, the aperture mainly is distributed in 160～390 micrometer ranges, comprcssive strength is about 6 MPas, after bone was implanted into for 16 weeks, the new bone growth area accounted for 35% of the damaged area of green bone.(see " experimentation of Porous Carbonated Hydroxyapatite Bone Cement " [doctorate paper] Beijing: Chinese People's Liberation Army General Hospital, 2002).In above-mentioned research, though bone cement material porosity increases, improved the vivo degradation speed and the osteogenic ability of material, failing resolving aperture and porosity increases the problem that the strength of materials brought reduces.Its comprcssive strength only is about 1/10th of common micropore calcium phosphate bone cement, can only be used for not carrying or the reparation of the bone defect that bearing capacity is very low.Dong Limin is according to the chitosan microball degradation in vivo speed characteristics faster than calcium phosphate bone cement, chitosan microball and calcium phosphate bone cement is compound, but preparation vivo degradation pore-forming, the early strength height, the fireballing calcium phosphate cement composite material of later stage degradation (" but preparation method of the calcium phosphate bone cement of degradation in vivo pore-forming ", number of patent application: 200510092982.2), make the intensity of composite bring up to 15MPa, but because the chitosan microball catabolite is alkalescence, thereby suppressed the degraded of calcium phosphate bone cement matrix, the intensity of composite and degradability await further to improve.
Summary of the invention
The present invention seeks to provides a kind of composite porous calcium phosphate bone cement and preparation method thereof in order to overcome the low and slow deficiency of degradation speed of porous calcium phosphate bone cement intensity in the past.This composite bone cement initial solidification intensity height, it is fast to implant later stage degradation, and degradation speed is adjustable, and the loose structure that the degraded back forms helps the new bone tissue growth and from the reconstruction of body bone.Can be used for bone defect repair and bone tissue engineering stent material, also can be as the tooth dental repair material.
The composite porous calcium phosphate bone cement that the present invention proposes is characterized in that, by orthophosphate skeleton cement solid powder with use Co
60Gamma-rays carries out the 3-hydroxybutyric acid-CO-3-hydroxyl pentanoate copolymer microsphere and the consolidation liquid of radiation treatment and forms; The percent by volume of each constituent is:
Calcium phosphate bone cement solid phase powder: 3-hydroxybutyric acid-CO-3-hydroxyl pentanoate copolymer microsphere is 5～50:50～95, and the volume ratio of consolidation liquid and calcium phosphate bone cement solid phase powder and 3-hydroxybutyric acid-CO-3-hydroxyl pentanoate copolymer microsphere total amount is 1:0.5～3.
The method of the preparation complex calcium phosphate bone cement as claimed in claim 1 that the present invention proposes, this method may further comprise the steps:
(1) preparation orthophosphate skeleton cement solid powder;
(2) preparation simulated body fluid;
(3) with PHBV microsphere Co
60Gamma-rays carries out radiation treatment;
(4) with behind the usefulness of the PHBV microsphere after (3) radiation treatment deionized water cleaning, drying, place glass container, the simulated body fluid that adds step (2) preparation, and the PHBV microsphere is fully immersed in the simulated body fluid, 36～38 ℃ of temperature, under the condition of humidity 60～90%, immersion treatment, remove old liquid, change the fresh simulated body fluid of same concentrations;
(5) the PHBV microsphere after step (4) immersion treatment is after cleaning repeatedly with deionized water or distilled water, 80～100 ℃ of oven dry;
(6) the PHBV microsphere after step (5) oven dry mixes 5～50:50～95 by volume with the solid phase powder of step (1) preparation, preparation PHBV microsphere/calcium phosphate bone cement composite powder;
(7) preparation buffer solution;
(8) preparation consolidation liquid: in the buffer solution of (7) preparation,, add analytical pure sodium bicarbonate and sodium alginate reagent respectively, be mixed with consolidation liquid in the ratio of 0.2～1.0 mole of per 1000 ml soln;
(9) the solid phase composite powder of step (6) preparation and the consolidation liquid of step (8) preparation are pressed solid-liquid volume ratio 0.5～3:1 preparation composite bone cement slurry.
Characteristics of the present invention and technique effect:
3-hydroxybutyric acid-CO-3-hydroxyl pentanoate copolymer (PHBV) is a kind of natural fat adoption ester that is present in the microbial cell, in vivo hydrolysis and enzyme digestion reaction can take place and degrades, and have excellent biological compatibility.The PHBV microsphere is added in the calcium phosphate bone cement matrix, and microsphere can play potentiation to matrix at the initial stage that material is implanted, and its degraded back forms porous support, helps growing into of osteocyte and osseous tissue.Simultaneously,, can promote to be the degraded of weakly alkaline calcium phosphate bone cement matrix, thereby accelerate the degraded of composite, help the formation and the reconstruction of new bone because its catabolite is faintly acid.
The present invention utilizes the PHBV microsphere degradation in vivo speed characteristics faster than calcium phosphate bone cement, will be through Co
60Gamma-ray irradiation and simulated body fluid surface-treated PHBV microsphere add in the calcium phosphate bone cement matrix, but the calcium phosphate cement composite material of the compound degradation in vivo pore-forming of preparation organic/inorganic.Common porous calcium phosphate bone cement material, owing to there are a large amount of holes, intensity is lower.In PHBV microsphere and calcium phosphate cement composite material, the initial stage have only micropore in the firming body, and porosity is low after solidifying, and intensity is higher.The body fluid passage that micropore forms, can impel PHBV microsphere degradation in vivo, along with the degraded in vivo of PHBV microsphere, macropore increases in the composite, porosity increases, thereby realizes that the method for employing vivo degradation pore-forming prepares the purpose of calcium phosphate cement composite material.After PHBV microsphere and calcium phosphate cement composite material implant, because the degraded of PHBV microsphere is very fast, can in the calcium phosphate bone cement matrix, form and the corresponding hole of microsphere size gradually, osteocyte can be grown in the hole, help the vascularization of material, and guarantee that nutrition supplies with to material inside organization, thereby promote the growth of new bone tissue and from the reconstruction of body bone.Simultaneously, because the catabolite of PHBV microsphere is faintly acid, can promote to be the degraded of weakly alkaline calcium phosphate bone cement matrix again, keep the acid-base balance of microenvironment in the body, improve the degradability of composite integral body, also avoided because the side effect such as inflammation that sour environment caused help the formation and the reconstruction of new bone.
Composite initial solidification intensity height of the present invention, it is fast to implant later stage degradation, and degradation speed is adjustable, and the loose structure that the degraded back forms helps the new bone tissue growth and from the reconstruction of body bone.
The present invention adopts the Co of various dose
60Gamma-rays carries out radiation treatment to the PHBV microsphere, and the speed with regulation and control PHBV microsphere degradation in vivo pore-forming can satisfy the requirement of the reparation of different bone defect to composite degradation speed.
The PHBV microsphere and the calcium phosphate cement composite material of the present invention's preparation are mainly used in bone defect repair and bone tissue engineering stent material, also can be as the tooth dental repair material.During use, the slurry that modulates directly can be injected the bone defect with syringe; Also slurry can be injected mould, behind external curing molding, replant defect to the marrow; Or with PHBV microsphere and calcium phosphate cement composite material at the external degradation pore-forming, preparation porous calcium phosphate bone cement material is used for bone tissue engineering scaffold.
The specific embodiment
Content of the present invention further describes as follows in conjunction with the embodiments:
A kind of composite porous calcium phosphate bone cement that the present invention proposes, by orthophosphate skeleton cement solid powder with use Co
60Gamma-rays carries out the 3-hydroxybutyric acid-CO-3-hydroxyl pentanoate copolymer microsphere and the consolidation liquid of radiation treatment and forms; The percent by volume of each constituent is:
Calcium phosphate bone cement solid phase powder: 3-hydroxybutyric acid-CO-3-hydroxyl pentanoate copolymer microsphere is 5～50:50～95, and the volume ratio of consolidation liquid and calcium phosphate bone cement solid phase powder and 3-hydroxybutyric acid-CO-3-hydroxyl pentanoate copolymer microsphere total amount is 1:0.5～3.
Described orthophosphate skeleton cement solid powder can be made up of α type tricalcium phosphate, dalcium biphosphate and calcium carbonate powder, and the mol ratio of each composition is:
α type tricalcium phosphate: dalcium biphosphate: calcium carbonate=(8～12): (1～2): (3～5) described Co that uses
60Gamma-rays is right-and dosage that hydroxybutyric acid-CO-3-hydroxyl pentanoate copolymer microsphere carries out radiation treatment can be 5～100kGy;
Preparation method of the present invention may further comprise the steps:
(1) (known calcium phosphate bone cement has and multiplely all can use the preparation orthophosphate skeleton cement solid powder, its preparation method is a known technology, for example a kind of concrete preparation method of orthophosphate skeleton cement solid powder is: α type tricalcium phosphate, dalcium biphosphate and calcium carbonate powder in molar ratio: α type tricalcium phosphate/dalcium biphosphate/calcium carbonate=(8～12)/(1～2)/(3～5) ball milling in anhydrous ethanol medium mixes 80～100 ℃ of oven dry);
(2) preparation simulated body fluid: in 1000 ml deionized water or distilled water, add sodium chloride 8.00～24.00 grams, sodium bicarbonate 0.35～1.01 gram, potassium chloride 0.23～0.69 gram, dipotassium hydrogen phosphate 0.23～0.69 gram, magnesium chloride 0.31～0.93 gram, calcium chloride 0.28g～0.84 gram, sodium sulfate 0.07～0.21 gram, Tris 6.06～18.18 grams are prepared simulated body fluid, and with the hydrochloric acid solution of 1 molar concentration the pH value of simulated body fluid are transferred to 7.2～7.4;
(3) with dosage the Co of 5～100kGy with PHBV microsphere (preparation method is a known technology)
60Gamma-rays carries out radiation treatment;
(4) with behind the usefulness of the PHBV microsphere after (3) radiation treatment deionized water cleaning, drying, place glass container, the simulated body fluid that adds step (2) preparation, and the PHBV microsphere is fully immersed in the simulated body fluid, 36～38 ℃ of temperature, under the condition of humidity 60～90%, immersion treatment 2～20 days, every 24～48 hours, remove old liquid during this time, change the fresh simulated body fluid of same concentrations;
(5) the PHBV microsphere after step (4) immersion treatment is after cleaning repeatedly with deionized water or distilled water, 80～100 ℃ of oven dry;
(6) the PHBV microsphere after step (5) oven dry mixes 5～50:50～95 by volume with the solid phase powder of step (1) preparation, preparation PHBV microsphere/calcium phosphate bone cement composite powder;
(7) with analytical pure sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate reagent and deionized water or distilled water compound concentration 0.2～1.0 mole etc. sodium dihydrogen phosphate and disodium hydrogen phosphate buffer solution or the potassium dihydrogen phosphate and the dipotassium hydrogen phosphate buffer solution of molar concentration;
(8) in the buffer solution of (7) preparation by the ratio of 0.2～1.0 mole of per 1000 ml soln, add analytical pure sodium bicarbonate and sodium alginate reagent respectively, prepare consolidation liquid;
(9) the solid phase composite powder of step (6) preparation and the consolidation liquid of step (8) preparation are pressed solid-liquid volume ratio 0.5～3:1 preparation composite bone cement slurry.
The bone cement slurry of above-mentioned preparation can directly be injected the bone defect with syringe, after also can injecting mold cured, replant defect to the marrow, or with PHBV microsphere and calcium phosphate cement composite material at the external degradation pore-forming, the preparation porous calcium phosphate bone cement is used for bone tissue engineering stent material.
Embodiment 1
(1) in molar ratio with α type tricalcium phosphate, dalcium biphosphate and calcium carbonate powder:
α type tricalcium phosphate: dalcium biphosphate: calcium carbonate=8:1:3 ball milling in anhydrous ethanol medium mixes, 80 ℃ of oven dry, preparation orthophosphate skeleton cement solid powder;
(2) in 1000 ml deionized water or distilled water, add sodium chloride 12 grams, sodium bicarbonate 0.53 gram, potassium chloride 0.34 gram, dipotassium hydrogen phosphate 0.34 gram, magnesium chloride 0.46 gram, calcium chloride 0.42 gram, sodium sulfate 0.1 gram, Tris 9.09 is prepared simulated body fluid, and with the hydrochloric acid solution of 1 molar concentration the pH value of simulated body fluid is transferred to 7.2;
(3) be the Co of 5kGy with PHBV microsphere dosage
60Gamma-rays carries out radiation treatment;
(4) with behind the usefulness of the PHBV microsphere after (3) radiation treatment deionized water cleaning, drying, place glass container, the simulated body fluid that adds step (2) preparation, and the PHBV microsphere is fully immersed in the simulated body fluid, 36 ℃ of temperature, under the condition of humidity 70%, immersion treatment 5 days, every 24 hours, remove old liquid during this time, change the fresh simulated body fluid of same concentrations;
(5) with the PHBV microsphere after step (4) immersion treatment, after cleaning repeatedly with deionized water or distilled water, 80～100 ℃ of oven dry;
(6) with the solid phase powder of the PHBV microsphere after step (5) oven dry and step (1) preparation by volume 5:95 mix, prepare PHBV microsphere/calcium phosphate bone cement composite powder;
(7) prepare the sodium dihydrogen phosphate/disodium hydrogen phosphate buffer solution of 0.2 molar concentration with analytical pure sodium dihydrogen phosphate, sodium hydrogen phosphate reagent and deionized water or distilled water;
(8) in the buffer solution of (7) preparation by the ratio of 0.2 mole of per 1000 ml soln, add analytical pure sodium bicarbonate and sodium alginate reagent respectively, prepare consolidation liquid;
(9) the solid phase composite powder of step (6) preparation and the consolidation liquid of step (8) preparation are prepared the composite bone cement slurry by solid-to-liquid ratio at 0.5: 1.
(10) the bone cement slurry with step (8) preparation directly injects the bone defect with syringe.
Embodiment 2
(1) in molar ratio with α type tricalcium phosphate, calcium hydrogen phosphate, tetracalcium phosphate and calcium carbonate powder:
α type tricalcium phosphate: calcium hydrogen phosphate: tetracalcium phosphate: calcium carbonate=10:1:1.5:3 ball milling in anhydrous ethanol medium mixes, 80 ℃ of oven dry, preparation orthophosphate skeleton cement solid powder;
(2) in 1000 ml deionized water or distilled water, add sodium chloride 8.00 grams, sodium bicarbonate 0.35 gram, potassium chloride 0.23 gram, dipotassium hydrogen phosphate 0.23 gram, magnesium chloride 0.31 gram, calcium chloride 0.28g gram, sodium sulfate 0.07 gram, Tris 6.06 grams are prepared simulated body fluid, and with the hydrochloric acid solution of 1 molar concentration the pH value of simulated body fluid are transferred to 7.3;
(3) be the Co of 25kGy with PHBV microsphere dosage
60Gamma-rays carries out radiation treatment;
(4) with behind the usefulness of the PHBV microsphere after (3) radiation treatment deionized water cleaning, drying, place glass container, the simulated body fluid that adds step (2) preparation, and the PHBV microsphere is fully immersed in the simulated body fluid, 37 ℃ of temperature, under the condition of humidity 80%, immersion treatment 10 days, every 36 hours, remove old liquid during this time, change the fresh simulated body fluid of same concentrations;
(5) with the PHBV microsphere after step (4) immersion treatment, after cleaning repeatedly with deionized water or distilled water, 80 ℃ of oven dry;
(6) with the solid phase powder of the PHBV microsphere after step (5) oven dry and step (1) preparation by volume 30:70 mix, prepare chitosan microball/calcium phosphate bone cement composite powder.
(7) prepare the potassium dihydrogen phosphate/dipotassium hydrogen phosphate buffer solution of 0.6 molar concentration with analytical pure potassium dihydrogen phosphate, dipotassium hydrogen phosphate reagent and deionized water or distilled water;
(8) in the buffer solution of (7) preparation by the ratio of 0.6 mole of per 1000 ml soln, add analytical pure sodium bicarbonate and sodium alginate reagent respectively, prepare consolidation liquid;
(9) the solid phase composite powder of step (6) preparation and the consolidation liquid of step (8) preparation are prepared the composite bone cement slurry by solid-to-liquid ratio 2:1.
(10) the bone cement slurry of step (9) preparation injects mould, 37 ℃ of temperature, solidified 6 hours under the condition of humidity 90%, place the simulated body fluid of step (2) preparation then, 37 ℃ of following immersion treatment of temperature 6 days, take out the back and clean up 80 ℃ of dry for standby with deionized water or distilled water.
Embodiment 3
(1) α type tricalcium phosphate, calcium hydrogen phosphate and calcium carbonate powder are in molar ratio:
α type tricalcium phosphate: calcium hydrogen phosphate: calcium carbonate=10:10:3 ball milling in anhydrous ethanol medium mixes; 80 ℃ of oven dry, the preparation orthophosphate skeleton cement solid powder;
(2) in 1000 ml deionized water or distilled water, add sodium chloride 24.00 grams, sodium bicarbonate～1.01 grams, potassium chloride 0.69 gram, dipotassium hydrogen phosphate 0.69 gram, magnesium chloride 0.93 gram, calcium chloride 0.84 gram, sodium sulfate 0.21 gram, Tris 18.18 grams are prepared simulated body fluid, and with the hydrochloric acid solution of 1 molar concentration the pH value of simulated body fluid are transferred to 7.4;
(3) be the Co of 100kGy with PHBV microsphere dosage
60Gamma-rays carries out radiation treatment;
(4) with behind the usefulness of the PHBV microsphere after (3) radiation treatment deionized water cleaning, drying, place glass container, the simulated body fluid that adds step (2) preparation, and the PHBV microsphere is fully immersed in the simulated body fluid, 36 ℃ of temperature, under the condition of humidity 70%, immersion treatment 15 days, every 48 hours, remove old liquid during this time, change the fresh simulated body fluid of same concentrations;
(5) with the PHBV microsphere after step (4) immersion treatment, after cleaning repeatedly with deionized water or distilled water, 80～100 ℃ of oven dry;
(6) with the solid phase powder of the PHBV microsphere after step (5) oven dry and step (1) preparation by volume 50:50 mix, prepare PHBV microsphere/calcium phosphate bone cement composite powder;
(7) prepare the sodium dihydrogen phosphate/disodium hydrogen phosphate buffer solution of 1.0 molar concentrations with analytical pure sodium dihydrogen phosphate, sodium hydrogen phosphate reagent and deionized water or distilled water;
(8) in the buffer solution of (7) preparation by the ratio of 1.0 moles of per 1000 ml solns, add analytical pure sodium bicarbonate and sodium alginate reagent respectively, prepare consolidation liquid;
(9) the solid phase composite powder of step (6) preparation and the consolidation liquid of step (8) preparation are prepared the composite bone cement slurry by solid-to-liquid ratio 3:1.
(10) the bone cement slurry with step (9) preparation directly injects mould with syringe, 37 ℃ of temperature, solidified 4 hours under the condition of humidity 90%, place the simulated body fluid of step (2) preparation then, 37 ℃ of following immersion treatment of temperature 6 days, take out the back and clean up with deionized water or distilled water, defect is to the marrow replanted in 80～100 ℃ of oven dry.
Claims (7)
1, a kind of composite porous calcium phosphate bone cement is characterized in that, by orthophosphate skeleton cement solid powder with use Co
60Gamma-rays carries out the 3-hydroxybutyric acid-CO-3-hydroxyl pentanoate copolymer microsphere and the consolidation liquid of radiation treatment and forms; The percent by volume of each constituent is:
Calcium phosphate bone cement solid phase powder: 3-hydroxybutyric acid-CO-3-hydroxyl pentanoate copolymer microsphere is 5～50: 50～95, and the volume ratio of consolidation liquid and calcium phosphate bone cement solid phase powder and 3-hydroxybutyric acid-CO-3-hydroxyl pentanoate copolymer microsphere total amount is 1: 0.5～3; Described orthophosphate skeleton cement solid powder is made up of α type tricalcium phosphate, dalcium biphosphate and calcium carbonate powder, and the mol ratio of each composition is:
α type tricalcium phosphate: dalcium biphosphate: calcium carbonate=(8～12): (1～2): (3～5); The described Co that uses
60Gamma-rays is right-and dosage that hydroxybutyric acid-CO-3-hydroxyl pentanoate copolymer microsphere carries out radiation treatment is 5～100kGy;
2, a kind of method for preparing complex calcium phosphate bone cement as claimed in claim 1, this method may further comprise the steps:
(1) preparation orthophosphate skeleton cement solid powder;
(2) preparation simulated body fluid;
(3) with PHBV microsphere Co
60Gamma-rays carries out radiation treatment;
(4) with behind the usefulness of the PHBV microsphere after (3) radiation treatment deionized water cleaning, drying, place glass container, the simulated body fluid that adds step (2) preparation, and the PHBV microsphere is fully immersed in the simulated body fluid, 36～38 ℃ of temperature, under the condition of humidity 60～90%, immersion treatment, remove old liquid, change the fresh simulated body fluid of same concentrations;
(5) the PHBV microsphere after step (4) immersion treatment is after cleaning repeatedly with deionized water or distilled water, 80～100 ℃ of oven dry;
(6) the PHBV microsphere after step (5) oven dry mixes 5～50:50～95 by volume with the solid phase powder of step (1) preparation, preparation PHBV microsphere/calcium phosphate bone cement composite powder;
(7) preparation buffer solution;
(8) preparation consolidation liquid: in the buffer solution of (7) preparation,, add analytical pure sodium bicarbonate and sodium alginate reagent respectively, be mixed with consolidation liquid in the ratio of 0.2～1.0 mole of per 1000 ml soln;
(9) the solid phase composite powder of step (6) preparation and the consolidation liquid of step (8) preparation are pressed solid-liquid volume ratio 0.5～3:1 preparation composite bone cement slurry.
3, preparation method according to claim 2, it is characterized in that: the concrete grammar of preparation orthophosphate skeleton cement solid powder is in the step (1): α type tricalcium phosphate, dalcium biphosphate and calcium carbonate powder in molar ratio: α type tricalcium phosphate/dalcium biphosphate/calcium carbonate=(8～12)/(1～2)/(3～5) ball milling in anhydrous ethanol medium mixes 80～100 ℃ of oven dry.
4, preparation method according to claim 2, it is characterized in that: in the step (2), the preparation of simulated body fluid according to: in 1000 ml deionized water or distilled water, add sodium chloride 8.00～24.00 grams, sodium bicarbonate 0.35～1.01 gram, potassium chloride 0.23～0.69 gram, dipotassium hydrogen phosphate 0.23～0.69 gram, magnesium chloride 0.31～0.93 gram, calcium chloride 0.28g～0.84 gram, sodium sulfate 0.07～0.21 gram, Tris 6.06～18.18 grams are mixed with simulated body fluid, and with the hydrochloric acid solution of 1 molar concentration the pH value of simulated body fluid are transferred to 7.2～7.4.
5, preparation method according to claim 2 is characterized in that: described step 2) use Co
60The dosage that gamma-rays carries out radiation treatment is 5～100kGy;
But 6, the calcium phosphate cement composite material preparation method of vivo degradation pore-forming according to claim 2 is characterized in that: in the described step (4), the time of described immersion treatment is 2～20 days, during every 24～48 hours.
7, preparation method according to claim 2 is characterized in that:
The concrete grammar of described step (7) preparation buffer solution is: with analytical pure sodium dihydrogen phosphate, sodium hydrogen phosphate reagent and deionized water or distilled water compound concentration 0.2～1.0 mole etc. the sodium dihydrogen phosphate and the disodium hydrogen phosphate buffer solution of molar concentration; Or with analytical pure potassium dihydrogen phosphate, dipotassium hydrogen phosphate reagent and deionized water or distilled water compound concentration 0.2～1.0 mole etc. the potassium dihydrogen phosphate and the dipotassium hydrogen phosphate buffer solution of molar concentration.
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| CN102515849B (en) * | 2011-12-16 | 2014-06-25 | 四川大学 | Porous bioceramic with calcium phosphate nanorods on surface layer and formation method for same |
| CN103394120B (en) * | 2013-07-31 | 2015-01-28 | 华南理工大学 | Calcium phosphate-based composite microsphere support and preparation method thereof |
| CN103709692B (en) * | 2013-11-18 | 2016-01-06 | 北京市射线应用研究中心 | Poly-epsilon-caprolactone/poly-(beta-hydroxy-butanoic acid-valerate) blend film and preparation method thereof |
| CN103611191B (en) * | 2013-11-29 | 2015-05-20 | 中山大学附属第一医院 | Moldable autologous bone paste and preparation method thereof |
| CN104940993B (en) * | 2015-06-24 | 2017-12-15 | 天津顺永泰锦科技有限公司 | A kind of injectable artificial bone of composite microencapsulation artificial cell |
| CN108114323A (en) * | 2018-01-24 | 2018-06-05 | 广西医科大学 | A kind of calcium phosphate bone cement compound of porous injectable |
| CN111773432A (en) * | 2019-04-04 | 2020-10-16 | 中国科学院金属研究所 | Magnesium-based amorphous-calcium phosphate/calcium silicate composite filler and preparation and application thereof |
| CN112546294A (en) * | 2020-12-03 | 2021-03-26 | 上海纳米技术及应用国家工程研究中心有限公司 | Preparation method of polyanhydride modified controllable biodegradable calcium phosphate bone cement, product and application thereof |
| CN113577369B (en) * | 2021-08-20 | 2022-07-22 | 山东明德生物医学工程有限公司 | Porous composite bone cement and preparation method thereof |
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