CN103251976B - Biomedical calcium sulfate based composite particle for slowly releasing metal ions and preparation method of biomedical calcium sulfate based composite particle - Google Patents
Biomedical calcium sulfate based composite particle for slowly releasing metal ions and preparation method of biomedical calcium sulfate based composite particle Download PDFInfo
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- CN103251976B CN103251976B CN201310162070.2A CN201310162070A CN103251976B CN 103251976 B CN103251976 B CN 103251976B CN 201310162070 A CN201310162070 A CN 201310162070A CN 103251976 B CN103251976 B CN 103251976B
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- metal ion
- calcium
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- phosphate
- tricalcium phosphate
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- 229910021645 metal ion Inorganic materials 0.000 title claims abstract description 115
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 title claims abstract description 90
- 239000011246 composite particle Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000000843 powder Substances 0.000 claims abstract description 73
- 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 abstract description 69
- 239000001506 calcium phosphate Substances 0.000 claims abstract description 64
- 229910000389 calcium phosphate Inorganic materials 0.000 claims abstract description 33
- 235000011010 calcium phosphates Nutrition 0.000 claims abstract description 33
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims abstract description 27
- 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 abstract description 27
- 239000002245 particle Substances 0.000 claims abstract description 4
- 238000005266 casting Methods 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract 3
- 239000011777 magnesium Substances 0.000 claims description 48
- 239000007864 aqueous solution Substances 0.000 claims description 45
- 235000011132 calcium sulphate Nutrition 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- 239000011575 calcium Substances 0.000 claims description 33
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 31
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- YTGLSPCIFCDMGL-UHFFFAOYSA-N [Ca].[Ca].O Chemical compound [Ca].[Ca].O YTGLSPCIFCDMGL-UHFFFAOYSA-N 0.000 claims description 30
- 239000011701 zinc Substances 0.000 claims description 27
- 239000002131 composite material Substances 0.000 claims description 26
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 25
- 239000001175 calcium sulphate Substances 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000008367 deionised water Substances 0.000 claims description 24
- 229910021641 deionized water Inorganic materials 0.000 claims description 24
- 229910052749 magnesium Inorganic materials 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 20
- 229910052712 strontium Inorganic materials 0.000 claims description 19
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims description 19
- 229910052691 Erbium Inorganic materials 0.000 claims description 18
- 229910052693 Europium Inorganic materials 0.000 claims description 18
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 18
- UYAHIZSMUZPPFV-UHFFFAOYSA-N erbium Chemical compound [Er] UYAHIZSMUZPPFV-UHFFFAOYSA-N 0.000 claims description 18
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 claims description 18
- 239000008187 granular material Substances 0.000 claims description 18
- 229910052746 lanthanum Inorganic materials 0.000 claims description 18
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 claims description 18
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 18
- 229910052710 silicon Inorganic materials 0.000 claims description 18
- 239000010703 silicon Substances 0.000 claims description 18
- 229910052725 zinc Inorganic materials 0.000 claims description 18
- PASHVRUKOFIRIK-UHFFFAOYSA-L calcium sulfate dihydrate Chemical compound O.O.[Ca+2].[O-]S([O-])(=O)=O PASHVRUKOFIRIK-UHFFFAOYSA-L 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 16
- GBNDTYKAOXLLID-UHFFFAOYSA-N zirconium(4+) ion Chemical compound [Zr+4] GBNDTYKAOXLLID-UHFFFAOYSA-N 0.000 claims description 16
- 239000011812 mixed powder Substances 0.000 claims description 15
- 230000002459 sustained effect Effects 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 7
- 229910002651 NO3 Inorganic materials 0.000 claims description 7
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 7
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 229910052726 zirconium Inorganic materials 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 33
- 229920000642 polymer Polymers 0.000 claims 12
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 9
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 9
- 229910052791 calcium Inorganic materials 0.000 claims 9
- 239000011574 phosphorus Substances 0.000 claims 9
- 229910052698 phosphorus Inorganic materials 0.000 claims 9
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 6
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 claims 6
- 238000010438 heat treatment Methods 0.000 claims 6
- 239000011259 mixed solution Substances 0.000 claims 6
- 239000002243 precursor Substances 0.000 claims 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 4
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims 3
- 239000002202 Polyethylene glycol Substances 0.000 claims 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims 3
- 229920002125 Sokalan® Polymers 0.000 claims 3
- 239000012670 alkaline solution Substances 0.000 claims 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 3
- 239000001110 calcium chloride Substances 0.000 claims 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims 3
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims 3
- 239000000920 calcium hydroxide Substances 0.000 claims 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims 3
- 229910001424 calcium ion Inorganic materials 0.000 claims 3
- 238000010276 construction Methods 0.000 claims 3
- 238000001816 cooling Methods 0.000 claims 3
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims 3
- 238000004108 freeze drying Methods 0.000 claims 3
- 239000004584 polyacrylic acid Substances 0.000 claims 3
- 229920001223 polyethylene glycol Polymers 0.000 claims 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims 3
- 235000011009 potassium phosphates Nutrition 0.000 claims 3
- 238000000926 separation method Methods 0.000 claims 3
- 239000001488 sodium phosphate Substances 0.000 claims 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims 3
- 238000003756 stirring Methods 0.000 claims 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims 3
- 238000005406 washing Methods 0.000 claims 3
- 229910019142 PO4 Inorganic materials 0.000 claims 2
- 239000010452 phosphate Substances 0.000 claims 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 2
- 210000000988 bone and bone Anatomy 0.000 abstract description 15
- 239000000463 material Substances 0.000 abstract description 14
- 239000002639 bone cement Substances 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 abstract description 2
- 239000004615 ingredient Substances 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 17
- 229910001427 strontium ion Inorganic materials 0.000 description 16
- PWYYWQHXAPXYMF-UHFFFAOYSA-N strontium(2+) Chemical compound [Sr+2] PWYYWQHXAPXYMF-UHFFFAOYSA-N 0.000 description 16
- 229910001425 magnesium ion Inorganic materials 0.000 description 13
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 9
- 230000015556 catabolic process Effects 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- 239000011572 manganese Substances 0.000 description 5
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 description 4
- 229910001437 manganese ion Inorganic materials 0.000 description 4
- 230000007547 defect Effects 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000000975 bioactive effect Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000004568 cement Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000007596 consolidation process Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 230000002188 osteogenic effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention discloses a biomedical calcium sulfate based composite particle for slowly releasing metal ions and a preparation method of the biomedical calcium sulfate based composite particle. The preparation method comprises the following steps of: thermally treating to obtain calcium sulfate powder containing metal ions and nanostructured calcium phosphate powder containing the metal ions in a wet chemical way, wherein a crystalline phase of the calcium sulfate powder containing the metal ions is alpha-calcium sulfate hemihydrate, and the crystalline phase of the nanostructured calcium phosphate powder containing the metal ions is any one or two of hydroxyapatite, alpha-tricalcium phosphate and beta-tricalcium phosphate; mixing the two groups of powder; and then casting into particles with adjustable components and ratio, wherein each particle is prepared through calcium sulfate containing the metal ions and nanostructured calcium phosphate containing the metal ions in a polyphase complex way. The composition of ingredients in the prepared calcium sulfate based composite particle containing the metal ions can be controlled, as well as the release rate of the metal ions; and the calcium sulfate based composite particle containing the metal ions can be widely applied to the field of biomedical materials such as bone filling materials and bone cement.
Description
Technical field
Calcium sulphate-based composite particles that the present invention relates to biomedical sustained-releasing metal ion-containing and preparation method thereof.
Background technology
Calcium sulfate has century-old history as artificial bone repair materials.Wherein, α-half-H 2 O calcium sulphate is with its good biocompatibility, bone conductibility, and the characteristics such as vivo degradation absorbability and high comprcssive strength become the study hotspot of inorganic bone repair materials and are widely used in Bone Defect Repari.But the calcium sulphate dihydrate formed after α-half-H 2 O calcium sulphate aquation degradation speed is in vivo still faster than the formation speed of new bone, and its Bone Defect Repari performance is subject to certain impact.
At present, be also widely used in Bone Defect Repari as the calcium phosphate of bioactive materials equally.Calcium phosphate has the constituent similar with human body hard tissue, and good biocompatibility and bone conductibility, but, its degraded slowly, overlong time is retained in body, do not reach requirement degradable within the treatment phase, have impact on growing into of new bone, this also becomes researcher and enterprise problem in the urgent need to address.
The problem of degrading is difficult to and the research carried out is a lot of for the too fast and calcium phosphate of calcium sulfate degraded.Main research and patent are all different with the degradation rate of calcium phosphate based on calcium sulfate, utilize the different adjustment degradation speed of two kinds of component ratios, thus make it to match with the body bone tissue speed of growth.A kind of new-type of inorganic bone grafting material disclosed in CN 101020085, is made up of by certain mass fraction proportioning bata-tricalcium phosphate and α-half-H 2 O calcium sulphate; Disclosed in CN 101843920 A, the preparation method of self pore-forming calcium phosphate cement bracket, joins injectable calcium phosphate bone cement by certain calcium sulfate, prepares novel composite bone cement;
Except control control degradation speed, metal ion also adds in calcium phosphate or calcium sulfate by some researchs, improves the osteogenic characteristics of material.The calcium phosphate composite powder of biomedical sustained-releasing metal ion-containing disclosed in CN 1799643, the calcium phosphate composite material of metal ion can as bioactive materials, after implanting, stimulatory protein(SP) is active, promote the growth of new bone, but calcium phosphate degradation speed slowly shortcoming do not improve.And disclosed in CN 102430147 A, mix the calcium sulfate material of strontium, although constantly can discharge strontium ion along with the degraded of this material, be conducive to promoting new bone formation, this material does not change the too fast shortcoming of calcium sulfate degradation speed yet.
Summary of the invention
A kind of too fast and calcium phosphate of calcium sulfate degraded that can improve is the object of the present invention is to provide to degrade slow shortcoming, again can release metal ions, stimulatory protein(SP) is active, promotes calcium sulphate-based composite particles of the biomedical sustained-releasing metal ion-containing of new bone growth and preparation method thereof.
The calcium sulphate-based composite particles of biomedical sustained-releasing metal ion-containing of the present invention, its each granule forms by the calcium sulfate of metal ion and the heterogeneous composite casting of calcium phosphate of nano-structured metal ion, wherein, the crystalline phase of the calcium sulphate powders of metal ion is α-half-H 2 O calcium sulphate, the crystalline phase of the calcium phosphate powder of nano-structured metal ion is hydroxyapatite, any phase or biphase in type alpha tricalcium phosphate and bata-tricalcium phosphate, the mol ratio of M/ (M+Ca) is 0.0001 ~ 0.1, M represents metal ion zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, one or more in silicon and zirconium.
The crystal grain of above-mentioned α-half-H 2 O calcium sulphate is 30 ~ 100 μm; The particle diameter of the calcium phosphate powder of nano-structured metal ion is 40nm ~ 500nm, and the single-phase crystallite dimension in powder is 5nm-40nm.
Prepare the method for the calcium sulphate-based composite particles of biomedical sustained-releasing metal ion-containing of the present invention, have following three kinds of schemes:
Scheme 1
Comprise the following steps:
1) metal ion compound soluble in water is dissolved in deionized water, obtains the aqueous solution of metal ion;
2) by step 1) the aqueous solution of metal ion and calcium sulphate dihydrate be uniformly mixed after put into reactor, wherein, the mol ratio of M/ (M+Ca) is 0.0001 ~ 0.1, M represents one or more in metallic zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon and zirconium ion, reaction temperature is 130 ~ 150 DEG C, and the response time is 6 ~ 10 hours, and then ethanol filters, dry, obtain the α-sulfate hemihydrate calcium powder of metal ion;
3) type alpha tricalcium phosphate of nano-structured metal ion, bata-tricalcium phosphate or type alpha tricalcium phosphate and bata-tricalcium phosphate composite powder is prepared by the method described in CN1799643;
4) by step 2) α-sulfate hemihydrate calcium powder of obtained metal ion and step 3) the type alpha tricalcium phosphate of nano-structured metal ion, bata-tricalcium phosphate or type alpha tricalcium phosphate and bata-tricalcium phosphate composite powder 1 ~ 4 to mix in mass ratio;
5) by step 4) mixed-powder and step 1) metal ion aqueous solution be uniformly mixed by solid-to-liquid ratio 2.5 ~ 3.5, be cast into granule.
Scheme 2
Comprise the following steps:
1) metal ion compound soluble in water is dissolved in deionized water, obtains the aqueous solution of metal ion;
2) by step 1) the aqueous solution of metal ion and calcium sulphate dihydrate be uniformly mixed after put into reactor, wherein, the mol ratio of M/ (M+Ca) is 0.0001 ~ 0.1, M represents one or more in metallic zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon and zirconium ion, reaction temperature is 130 ~ 150 DEG C, and the response time is 6 ~ 10 hours, and then ethanol filters, dry, obtain the α-sulfate hemihydrate calcium powder of metal ion;
3) hydroxyapatite of nano-structured metal ion, type alpha tricalcium phosphate or hydroxyapatite and type alpha tricalcium phosphate composite powder is prepared by the method described in CN1799643;
4) by step 2) α-sulfate hemihydrate calcium powder of obtained metal ion and step 3) the hydroxyapatite of nano-structured metal ion, type alpha tricalcium phosphate or hydroxyapatite and type alpha tricalcium phosphate composite powder 1 ~ 4 to mix in mass ratio;
5) by step 4) mixed-powder and step 1) metal ion aqueous solution be uniformly mixed by solid-to-liquid ratio 2.5 ~ 3.5, be cast into granule.
Scheme 3
Comprise the following steps:
1) metal ion compound soluble in water is dissolved in deionized water, obtains the aqueous solution of metal ion;
2) by step 1) the aqueous solution of metal ion and calcium sulphate dihydrate be uniformly mixed after put into reactor, wherein, the mol ratio of M/ (M+Ca) is 0.0001 ~ 0.1, M represents one or more in metallic zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon and zirconium ion, reaction temperature is 130 ~ 150 DEG C, and the response time is 6 ~ 10 hours, and then ethanol filters, dry, obtain the α-sulfate hemihydrate calcium powder of metal ion;
3) hydroxyapatite of nano-structured metal ion, bata-tricalcium phosphate or hydroxyapatite and bata-tricalcium phosphate composite powder is prepared by the method described in CN1799643;
4) by step 2) α-sulfate hemihydrate calcium powder of obtained metal ion and step 3) the hydroxyapatite of nano-structured metal ion, bata-tricalcium phosphate or hydroxyapatite and bata-tricalcium phosphate composite powder 1 ~ 4 to mix in mass ratio;
5) by step 4) mixed-powder and step 1) metal ion aqueous solution be uniformly mixed by solid-to-liquid ratio 2.5 ~ 3.5, be cast into granule.
In above-mentioned three kinds of preparation methoies, described metal ion compound soluble in water is zinc, the soluble nitrate of strontium, magnesium, lanthanum, europium, erbium, manganese, silicon or zirconium ion or chloride.
Compared with prior art, the present invention has following useful technique effect:
Calcium sulphate-based composite particles of the present invention can control the proportion of composing of calcium sulfate and calcium phosphate in granule by Controlling Technology condition, thus controls biological activity and the biodegradation rate of calcium sulphate-based composite particles; In addition, in the present invention, by the kind and the content that regulate the content of the metal ion in the mol ratio of M/ (M+Ca) in reactant and consolidation liquid can regulate metal ion in composite particles, to reach the object of controlled Metal ion release.Can bone cell differentiation be promoted, growth by metal ion, thus the healing accelerating osseous tissue.The calcium sulphate-based composite particles of slow release metal ion prepared by the present invention is simple to operate, is easy to industrialization, can be applicable to the field of biomedical materials such as hard tissue substituting material, filling material of bone, bone cement and coating.
Detailed description of the invention
Embodiment 1
1) by Zn (NO
3)
24H
2o is dissolved in deionized water, obtains Zn (NO
3)
24H
2the aqueous solution of O;
2) by Zn (NO
3)
24H
2put into reactor after the aqueous solution of O and calcium sulphate dihydrate are uniformly mixed, wherein, the mol ratio of Zn/ (Zn+Ca) is 0.02, reaction temperature is 130 DEG C, and the response time is 10 hours, and then ethanol filters, dry, obtain the α-sulfate hemihydrate calcium powder containing zinc ion.
3) the nano-structured type alpha tricalcium phosphate powder containing zinc ion is prepared by the method described in CN1799643;
4) by step 2) the obtained α-sulfate hemihydrate calcium powder containing zinc ion and step 3) the obtained nano-structured type alpha tricalcium phosphate powder containing zinc ion, 3:1 mixes in mass ratio, by mixed powder and 0.02M step 1) zinc ion aqueous solution be 2.5 to be uniformly mixed by solid-to-liquid ratio, be cast into granule.
Embodiment 2
1) by Mg (NO
3)
26H
2o is dissolved in deionized water, obtains Mg (NO
3)
26H
2the aqueous solution of O;
2) by Mg (NO
3)
26H
2put into reactor after the aqueous solution of O and calcium sulphate dihydrate are uniformly mixed, wherein, the mol ratio of Mg/ (Mg+Ca) is 0.03, reaction temperature is 140 DEG C, and the response time is 8 hours, and then ethanol filters, dry, obtain the α-sulfate hemihydrate calcium powder containing magnesium ion.
3) prepare by the method described in CN1799643 nano-structured containing 50% type alpha tricalcium phosphate of magnesium ion and the calcium phosphate composite powder of 50% bata-tricalcium phosphate;
4) by step 2) the obtained α-sulfate hemihydrate calcium powder containing magnesium ion and step 3) obtained containing 50% type alpha tricalcium phosphate of magnesium ion and the calcium phosphate composite powder of 50% bata-tricalcium phosphate, 4:1 mixes in mass ratio, by mixed powder and 0.02M step 1) magnesium ion aqueous solution be 3.0 to be uniformly mixed by solid-to-liquid ratio, be cast into granule.
Embodiment 3
1) by same ratio Mg (NO
3)
26H
2o and Zn (NO
3)
24H
2o is dissolved in deionized water, obtains Mg (NO
3)
26H
2o and Zn (NO
3)
24H
2the aqueous solution of O;
2) reactor is put into after above-mentioned aqueous solution and calcium sulphate dihydrate being uniformly mixed, wherein, the mol ratio of Mg+Zn/ (Mg+Zn+Ca) is 0.04, reaction temperature is 150 DEG C, response time is 6 hours, then ethanol filters, and dries, and obtains the α-sulfate hemihydrate calcium powder containing magnesium and zinc ion.
3) prepare by the method described in CN1799643 nano-structured containing magnesium and zinc ion bata-tricalcium phosphate powder;
4) by step 2) the obtained α-sulfate hemihydrate calcium powder containing zinc ion and step 3) obtained containing magnesium and zinc ion bata-tricalcium phosphate powder, 3:1 mixes in mass ratio, by mixed powder and 0.02M step 1) zinc ion aqueous solution be 2.5 to be uniformly mixed by solid-to-liquid ratio, be cast into granule.
Embodiment 4
1) by Mn (NO
3)
2be dissolved in deionized water, obtain Mn (NO
3)
2aqueous solution;
2) by Mn (NO
3)
2aqueous solution and calcium sulphate dihydrate be uniformly mixed after put into reactor, wherein, the mol ratio of Mn/ (Mn+Ca) is 0.02, reaction temperature is 130 DEG C, and the response time is 10 hours, and then ethanol filters, dry, obtain the α-sulfate hemihydrate calcium powder containing zinc ion.
3) the nano-structured hydroxyapatite powder containing manganese ion is prepared by the method described in CN1799643;
4) by step 2) the obtained α-sulfate hemihydrate calcium powder containing manganese ion and step 3) hydroxyapatite powder of obtained manganese ion, 2.5:1 mixes in mass ratio, by mixed powder and 0.02M step 1) manganese ion aqueous solution be 2.5 to be uniformly mixed by solid-to-liquid ratio, be cast into granule.
Embodiment 5
1) by Sr (NO
3)
2be dissolved in deionized water, obtain Sr (NO
3)
2aqueous solution;
2) by Sr (NO
3)
2aqueous solution and calcium sulphate dihydrate be uniformly mixed after put into reactor, wherein, the mol ratio of Sr/ (Sr+Ca) is 0.03, reaction temperature is 140 DEG C, and the response time is 8 hours, and then ethanol filters, dry, obtain the α-sulfate hemihydrate calcium powder containing strontium ion.
3) prepare by the method described in CN1799643 nano-structured containing 40% type alpha tricalcium phosphate of strontium ion and the calcium phosphate composite powder of 60% hydroxyapatite;
4) by step 2) the obtained α-sulfate hemihydrate calcium powder containing strontium ion and step 3) obtained containing 40% type alpha tricalcium phosphate of strontium ion and the calcium phosphate composite powder of 60% hydroxyapatite, 4:1 mixes in mass ratio, by mixed powder and 0.02M step 1) strontium ion aqueous solution be 3.0 to be uniformly mixed by solid-to-liquid ratio, be cast into granule.
Embodiment 6
1) by same ratio Mg (NO
3)
26H
2o and Sr (NO
3)
2be dissolved in deionized water, obtain Mg (NO
3)
26H
2o and Sr (NO
3)
2aqueous solution;
2) reactor is put into after above-mentioned aqueous solution and calcium sulphate dihydrate being uniformly mixed, wherein, the mol ratio of Mg+Sr/ (Mg+Sr+Ca) is 0.04, reaction temperature is 150 DEG C, response time is 6 hours, then ethanol filters, and dries, and obtains the α-sulfate hemihydrate calcium powder containing magnesium and strontium ion.
3) prepare by the method described in CN1799643 nano-structured containing zinc ion type alpha tricalcium phosphate powder;
4) by step 2) obtained α-sulfate hemihydrate calcium powder containing magnesium and strontium ion and step 3) obtained containing zinc ion type alpha tricalcium phosphate powder, 3:1 mixes in mass ratio, by mixed powder and 0.02M step 1) zinc ion aqueous solution be 2.5 to be uniformly mixed by solid-to-liquid ratio, be cast into granule.
Embodiment 7
1) by Sr (NO
3)
2be dissolved in deionized water, obtain Sr (NO
3)
2aqueous solution;
2) by Sr (NO
3)
2aqueous solution and calcium sulphate dihydrate be uniformly mixed after put into reactor, wherein, the mol ratio of Sr/ (Sr+Ca) is 0.02, reaction temperature is 130 DEG C, and the response time is 10 hours, and then ethanol filters, dry, obtain the α-sulfate hemihydrate calcium powder containing strontium ion.
3) the nano-structured hydroxyapatite powder containing strontium ion is prepared by the method described in CN1799643;
4) by step 2) the obtained α-sulfate hemihydrate calcium powder containing strontium ion and step 3) hydroxyapatite powder of obtained strontium ion, 2.5:1 mixes in mass ratio, by mixed powder and 0.02M step 1) strontium ion aqueous solution be 2.5 to be uniformly mixed by solid-to-liquid ratio, be cast into granule.
Embodiment 8
1) by Mg (NO
3)
26H
2o is dissolved in deionized water, obtains Mg (NO
3)
26H
2the aqueous solution of O;
2) by Mg (NO
3)
26H
2put into reactor after the aqueous solution of O and calcium sulphate dihydrate are uniformly mixed, wherein, the mol ratio of Mg/ (Mg+Ca) is 0.03, reaction temperature is 140 DEG C, and the response time is 8 hours, and then ethanol filters, dry, obtain the α-sulfate hemihydrate calcium powder containing strontium ion.
3) prepare by the method described in CN1799643 nano-structured containing 40% bata-tricalcium phosphate of magnesium ion and the calcium phosphate composite powder of 60% hydroxyapatite;
4) by step 2) the obtained α-sulfate hemihydrate calcium powder containing magnesium ion and step 3) obtained containing 40% bata-tricalcium phosphate of magnesium ion and the calcium phosphate composite powder of 60% hydroxyapatite, 4:1 mixes in mass ratio, by mixed powder and 0.02M step 1) magnesium ion aqueous solution be 3.0 to be uniformly mixed by solid-to-liquid ratio, be cast into granule.
Embodiment 9
1) by same ratio Mg (NO
3)
26H
2o and Sr (NO
3)
2be dissolved in deionized water, obtain Mg (NO
3)
26H
2o and Sr (NO
3)
2aqueous solution;
2) by Mg (NO
3)
26H
2o and Sr (NO
3)
2aqueous solution and calcium sulphate dihydrate be uniformly mixed after put into reactor, wherein, the mol ratio of Mg+Sr/ (Mg+Sr+Ca) is 0.04, reaction temperature is 150 DEG C, and the response time is 6 hours, and then ethanol filters, dry, obtain the α-sulfate hemihydrate calcium powder containing magnesium and strontium ion.
3) prepare by the method described in CN1799643 nano-structured containing zinc ion bata-tricalcium phosphate powder;
4) by step 2) obtained α-sulfate hemihydrate calcium powder containing magnesium and strontium ion and step 3) obtained containing zinc ion bata-tricalcium phosphate powder, 3:1 mixes in mass ratio, by mixed powder and 0.02M step 1) zinc ion aqueous solution be 2.5 to be uniformly mixed by solid-to-liquid ratio, be cast into granule.
Claims (8)
1. the calcium sulphate-based composite particles of biomedical sustained-releasing metal ion-containing, it is characterized in that its each granule forms by the calcium sulfate of metal ion and the heterogeneous composite casting of calcium phosphate of nano-structured metal ion, wherein, the crystalline phase of the calcium sulphate powders of metal ion is α-half-H 2 O calcium sulphate, the crystalline phase of the calcium phosphate powder of nano-structured metal ion is hydroxyapatite, any phase or biphase in type alpha tricalcium phosphate and bata-tricalcium phosphate, the mol ratio of M/ (M+Ca) is 0.0001 ~ 0.1, M represents metal ion zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, one or more in silicon and zirconium.
2. the calcium sulphate-based composite particles of biomedical sustained-releasing metal ion-containing according to claim 1, is characterized in that the crystal grain of described α-half-H 2 O calcium sulphate is 30 ~ 100 μm; The particle diameter of the calcium phosphate powder of nano-structured metal ion is 40nm ~ 500nm, and the single-phase crystallite dimension in powder is 5nm-40nm.
3. prepare the method for the calcium sulphate-based composite particles of biomedical sustained-releasing metal ion-containing according to claim 1, comprise the following steps:
1) metal ion compound soluble in water is dissolved in deionized water, obtains the aqueous solution of metal ion;
2) by step 1) the aqueous solution of metal ion and calcium sulphate dihydrate be uniformly mixed after put into reactor, wherein, the mol ratio of M/ (M+Ca) is 0.0001 ~ 0.1, M represents one or more in metallic zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon and zirconium ion, reaction temperature is 130 ~ 150 DEG C, and the response time is 6 ~ 10 hours, and then ethanol filters, dry, obtain the α-sulfate hemihydrate calcium powder of metal ion;
3) type alpha tricalcium phosphate of nano-structured metal ion, bata-tricalcium phosphate or type alpha tricalcium phosphate and bata-tricalcium phosphate composite powder is prepared by following method;
A) lime nitrate or calcium chloride or calcium hydroxide are dissolved in deionized water are mixed with calcium source solution, ammonium hydrogen phosphate or sodium phosphate or phosphoric acid or potassium phosphate are dissolved in deionized water are mixed with phosphorus source solution, the nitrate of zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon or zirconium ion or chloride soluble compounds are dissolved in deionized water and form metal ion solution, at above-mentioned calcium source solution, phosphorus source solution and metal ion solution are placed in 0 ~ 20 DEG C respectively;
B) calcium source solution, metal ion solution and polymer mixed are formed mixed solution, at being placed in 0 ~ 20 DEG C, wherein the mol ratio of M/ (M+Ca) is one or more that 0.0001 ~ 0.1, M represents in metallic zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon, zirconium ion; The mol ratio of polymer and calcium ion is 1: 10 ~ 10: 1, and polymer calculates with the molal quantity of construction unit, and said polymer is Polyethylene Glycol, polyvinyl alcohol or polyacrylic acid;
C) phosphorus source solution is added dropwise in the mixed solution b), Ca/P mol ratio is 1.50, alkaline solution adjust ph 7 ~ 12 is dripped during reaction, react and carry out under constantly stirring, reaction temperature remains on 0 DEG C ~ 20 DEG C, response time is 5 minutes ~ 48 hours, separation after reaction, washing, lyophilization, obtains metal ion amorphous calcium phosphate precursor;
D) by metal ion amorphous calcium phosphate precursor with the heating rate of 5 DEG C/min ~ 50 DEG C/min, heat treatment 10 minutes ~ 5 hours at 700 DEG C ~ 900 DEG C, last furnace cooling, obtains the type alpha tricalcium phosphate of metal ion, bata-tricalcium phosphate or type alpha tricalcium phosphate and bata-tricalcium phosphate composite powder;
4) by step 2) α-sulfate hemihydrate calcium powder of obtained metal ion and step 3) the type alpha tricalcium phosphate of nano-structured metal ion, bata-tricalcium phosphate or type alpha tricalcium phosphate and bata-tricalcium phosphate composite powder 1 ~ 4 to mix in mass ratio;
5) by step 4) mixed-powder and step 1) metal ion aqueous solution be uniformly mixed by solid-to-liquid ratio 2.5 ~ 3.5, be cast into granule.
4., by the preparation method of the calcium sulphate-based composite particles of biomedical sustained-releasing metal ion-containing according to claim 3, it is characterized in that described metal ion compound soluble in water is soluble nitrate or the chloride of zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon or zirconium ion.
5. prepare the method for the calcium sulphate-based composite particles of biomedical sustained-releasing metal ion-containing according to claim 1, its feature comprises the following steps:
1) metal ion compound soluble in water is dissolved in deionized water, obtains the aqueous solution of metal ion;
2) by step 1) the aqueous solution of metal ion and calcium sulphate dihydrate be uniformly mixed after put into reactor, wherein, the mol ratio of M/ (M+Ca) is 0.0001 ~ 0.1, M represents one or more in metallic zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon and zirconium ion, reaction temperature is 130 ~ 150 DEG C, and the response time is 6 ~ 10 hours, and then ethanol filters, dry, obtain the α-sulfate hemihydrate calcium powder of metal ion;
3) hydroxyapatite of nano-structured metal ion, type alpha tricalcium phosphate or hydroxyapatite and type alpha tricalcium phosphate composite powder is prepared by following method:
A) lime nitrate or calcium chloride or calcium hydroxide are dissolved in deionized water are mixed with calcium source solution, ammonium hydrogen phosphate or sodium phosphate or phosphoric acid or potassium phosphate are dissolved in deionized water are mixed with phosphorus source solution, the nitrate of zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon or zirconium ion or chloride soluble compounds are dissolved in deionized water and form metal ion solution, potassium carbonate or sodium carbonate formation soluble in water are contained the solution of carbonate, at above-mentioned calcium source solution, phosphorus source solution, metal ion solution and the solution containing carbonate are placed in 0 ~ 20 DEG C respectively;
B) calcium source solution, metal ion solution and polymer mixed are formed mixed solution, at being placed in 0 ~ 20 DEG C, wherein the mol ratio of M/ (M+Ca) is one or more that 0.0001 ~ 0.1, M represents in metallic zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon, zirconium ion; The mol ratio of polymer and calcium ion is 1: 10 ~ 10: 1, and polymer calculates with the molal quantity of construction unit, and said polymer is Polyethylene Glycol, polyvinyl alcohol or polyacrylic acid;
C) by phosphorus source solution with containing in the mixed solution be added dropwise to after the mixing of carbanion solution b), Ca/P mol ratio is 1.50 ~ 1.67, carbonate and phosphate radical mol ratio are 15% ~ 70%, alkaline solution adjust ph 7 ~ 12 is dripped during reaction, react and carry out under constantly stirring, reaction temperature is 0 ~ 20 DEG C, and the response time is 5 minutes ~ 48 hours, separation after reaction, washing, lyophilization, obtain metal ion amorphous calcium phosphate precursor;
D) by metal ion amorphous calcium phosphate precursor with the heating rate of 5 DEG C/min ~ 50 DEG C/min, heat treatment 10 minutes ~ 5 hours at 800 DEG C, last furnace cooling, obtains the hydroxyapatite of metal ion, type alpha tricalcium phosphate or hydroxyapatite and type alpha tricalcium phosphate composite powder;
4) by step 2) α-sulfate hemihydrate calcium powder of obtained metal ion and step 3) the hydroxyapatite of nano-structured metal ion, type alpha tricalcium phosphate or hydroxyapatite and type alpha tricalcium phosphate composite powder 1 ~ 4 to mix in mass ratio;
5) by step 4) mixed-powder and step 1) metal ion aqueous solution be uniformly mixed by solid-to-liquid ratio 2.5 ~ 3.5, be cast into granule.
6., by the preparation method of the calcium sulphate-based composite particles of biomedical sustained-releasing metal ion-containing according to claim 5, it is characterized in that described metal ion compound soluble in water is soluble nitrate or the chloride of zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon or zirconium ion.
7. prepare the method for the calcium sulphate-based composite particles of biomedical sustained-releasing metal ion-containing according to claim 1, its feature comprises the following steps:
1) metal ion compound soluble in water is dissolved in deionized water, obtains the aqueous solution of metal ion;
2) by step 1) the aqueous solution of metal ion and calcium sulphate dihydrate be uniformly mixed after put into reactor, wherein, the mol ratio of M/ (M+Ca) is 0.0001 ~ 0.1, M represents one or more in metallic zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon and zirconium ion, reaction temperature is 130 ~ 150 DEG C, and the response time is 6 ~ 10 hours, and then ethanol filters, dry, obtain the α-sulfate hemihydrate calcium powder of metal ion;
3) hydroxyapatite of nano-structured metal ion, bata-tricalcium phosphate or hydroxyapatite and bata-tricalcium phosphate composite powder is prepared by following method;
A) lime nitrate or calcium chloride or calcium hydroxide are dissolved in deionized water are mixed with calcium source solution, ammonium hydrogen phosphate or sodium phosphate or phosphoric acid or potassium phosphate are dissolved in deionized water are mixed with phosphorus source solution, the nitrate of zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon or zirconium ion or chloride soluble compounds are dissolved in deionized water and form metal ion solution, potassium carbonate or sodium carbonate formation soluble in water are contained the solution of carbonate, at above-mentioned calcium source solution, phosphorus source solution, metal ion solution and the solution containing carbonate are placed in 0 ~ 20 DEG C respectively;
B) calcium source solution, metal ion solution and polymer mixed are formed mixed solution, at being placed in 0 ~ 20 DEG C, wherein the mol ratio of M/ (M+Ca) is one or more that 0.0001 ~ 0.1, M represents in metallic zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon, zirconium ion; The mol ratio of polymer and calcium ion is 1: 10 ~ 10: 1, and polymer calculates with the molal quantity of construction unit, and said polymer is Polyethylene Glycol, polyvinyl alcohol or polyacrylic acid;
C) by phosphorus source solution with containing in the mixed solution be added dropwise to after the mixing of carbanion solution b), Ca/P mol ratio is 1.50 ~ 1.67, carbonate and phosphate radical mol ratio are 15% ~ 70%, alkaline solution adjust ph 7 ~ 12 is dripped during reaction, react and carry out under constantly stirring, reaction temperature is 0 ~ 20 DEG C, and the response time is 5 minutes ~ 48 hours, separation after reaction, washing, lyophilization, obtain metal ion amorphous calcium phosphate precursor;
D) by metal ion amorphous calcium phosphate precursor with the heating rate of 5 DEG C/min ~ 50 DEG C/min, heat treatment 10 minutes ~ 5 hours at 900 DEG C, last furnace cooling, obtains the hydroxyapatite of metal ion, bata-tricalcium phosphate or hydroxyapatite and bata-tricalcium phosphate composite powder;
4) by step 2) α-sulfate hemihydrate calcium powder of obtained metal ion and step 3) the hydroxyapatite of nano-structured metal ion, bata-tricalcium phosphate or hydroxyapatite and bata-tricalcium phosphate composite powder 1 ~ 4 to mix in mass ratio;
5) by step 4) mixed-powder and step 1) metal ion aqueous solution be uniformly mixed by solid-to-liquid ratio 2.5 ~ 3.5, be cast into granule.
8., by the preparation method of the calcium sulphate-based composite particles of biomedical sustained-releasing metal ion-containing according to claim 7, it is characterized in that described metal ion compound soluble in water is soluble nitrate or the chloride of zinc, strontium, magnesium, lanthanum, europium, erbium, manganese, silicon or zirconium ion.
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