CN1241871C - Medicinal bio-decomposable ceramics - Google Patents
Medicinal bio-decomposable ceramics Download PDFInfo
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- CN1241871C CN1241871C CN 03110229 CN03110229A CN1241871C CN 1241871 C CN1241871 C CN 1241871C CN 03110229 CN03110229 CN 03110229 CN 03110229 A CN03110229 A CN 03110229A CN 1241871 C CN1241871 C CN 1241871C
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- calcium phosphate
- secondary calcium
- conducting system
- bone
- biodegradable
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- 239000000919 ceramic Substances 0.000 title abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 210000000988 bone and bone Anatomy 0.000 claims description 73
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 44
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 13
- 102000013275 Somatomedins Human genes 0.000 claims description 13
- 239000000843 powder Substances 0.000 claims description 13
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical class N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 claims description 12
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 230000008468 bone growth Effects 0.000 claims description 9
- 230000001939 inductive effect Effects 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- 230000006835 compression Effects 0.000 claims description 6
- 238000007906 compression Methods 0.000 claims description 6
- 230000008929 regeneration Effects 0.000 claims description 6
- 238000011069 regeneration method Methods 0.000 claims description 6
- LUZSPGQEISANPO-UHFFFAOYSA-N butyltin Chemical compound CCCC[Sn] LUZSPGQEISANPO-UHFFFAOYSA-N 0.000 claims description 5
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical compound O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 abstract description 40
- 239000005057 Hexamethylene diisocyanate Substances 0.000 abstract description 6
- 239000011575 calcium Substances 0.000 abstract description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract 2
- 229910052791 calcium Inorganic materials 0.000 abstract 2
- 238000002411 thermogravimetry Methods 0.000 description 19
- 239000001506 calcium phosphate Substances 0.000 description 17
- 229910000389 calcium phosphate Inorganic materials 0.000 description 17
- 235000011010 calcium phosphates Nutrition 0.000 description 17
- 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 description 17
- 238000004458 analytical method Methods 0.000 description 15
- 210000000963 osteoblast Anatomy 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 9
- 230000004819 osteoinduction Effects 0.000 description 9
- 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 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 230000004820 osteoconduction Effects 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 230000012010 growth Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 210000002536 stromal cell Anatomy 0.000 description 5
- 230000017423 tissue regeneration Effects 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000000962 organic group Chemical group 0.000 description 4
- 230000001172 regenerating effect Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 230000002950 deficient Effects 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 238000004679 31P NMR spectroscopy Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium;phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 210000004409 osteocyte Anatomy 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000008263 repair mechanism Effects 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 208000006735 Periostitis Diseases 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 210000002805 bone matrix Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000004455 differential thermal analysis Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 210000003692 ilium Anatomy 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000005389 magnetism Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 230000002188 osteogenic effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 210000003460 periosteum Anatomy 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000000930 thermomechanical effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Abstract
The present invention relates to medicinal bio-decomposable ceramics which comprise calcium hydrophosphate whose surface is modified by organic molecules, wherein the organic molecules are hexamethylenediisocyanate (HMDI), and the hexamethylenediisocyanate is grafted on the calcium hydrophosphate in a covalent bond mode. The present invention also relates to a method for manufacturing the medicinal bio-decomposable ceramics. In addition, the medicinal bio-decomposable ceramics can be applied to repairing skeletal tissue. Thus, the present invention relates to a method and a device for repairing skeletal tissue, and a conducting system for skeleton tissue repairing medicine.
Description
Technical field
The invention relates to a kind of pharmaceutical Biodegradable pottery and manufacture method thereof, refer to a kind of pharmaceutical Biodegradable pottery and manufacture method thereof that is applicable to that bone tissue repairs especially.
The present invention also is relevant to method and the device that a kind of bone tissue repairs, and the conducting system of a kind of osseous tissue and bone tissue's repair medicine.
Background technology
By discovering in the past, the source that new bone generates (neo-osteogenesis) has three kinds: first kind is the osteocyte transplanting of living; Second kind is osseous tissue guiding generation (osteoconduction), and meaning promptly makes bone defective region osteocyte length on every side to the framework of transplant; The third induces generation (osteoinduction) for osseous tissue, and meaning promptly makes mesenchymal cell (mesenchymal cell) influenced by some somatomedin and is divided into osteoblast, and then produces osseous tissue.
Generally speaking, the treatment that bone is damaged must be filled a suitable material usually, to keep near the physical condition of organizing the damaged place.Optimal filler is an autograft, and the osseous tissue guiding generates (osteoconduction) and osseous tissue is induced generation (osteoinduction) effect because it can have concurrently; But source of graft and quantity limit all to some extent.Therefore, the scientist in this field all makes great efforts to research and develop the novel material that can be used as bone ilium surrogate in recent years, calcium phosphate and bioactivity glass have been found at present, all have biocompatibility and biological activity, can form chemical bonded refractory with bone, and successfully be applied to the expansion of clinical bone defect repairing and osseous tissue.Yet these pharmaceutical bone potteries only have the osseous tissue guiding and generate (osteoconduction) ability, but lack osseous tissue and induce generation (osteoinduction) ability, can't have two-phase formula repair mechanism as autograft; This two-phase formula repair mechanism comprises osteoblast directly is transferred on the graft (graft), and will induce with the factor of growing and discharge in the bone matrix of graft, makes osteoblast can further generate osseous tissue.
Therefore, the emphasis that requires for pharmaceutical bone pottery just is to seek a kind of good conducting system at present, preferably this bone pottery itself is a good conducting system, the bone growth medicine that makes this bone pottery can accept the somatomedin of tissue itself or add, and then have osseous tissue and induce generation (osteoinduction) ability.
In addition, the bone pottery that is used for bone tissue's reparation usefulness is preferably Biodegradable or Bioabsorbable, and tissue to be repaired does not just need to carry out second operation again it is taken out after generating.Monolithic block and disk system have been used at present, as the conducting system of a biological decomposability.Right monolithic block can stop up the space of marrow, and this locates just that bone precursor cell content enriches part, and therefore the effect of repairing for bone tissue is just had a greatly reduced quality.
Therefore, still need a kind of new bone stupalith at present, can be used as a good conducting system, make this bone pottery have osseous tissue guiding generation (osteoconduction) simultaneously and induce generation (osteoinduction) ability with osseous tissue.This material is also had a Biodegradable simultaneously, and granular size can not stopped up the marrow space, is fit to osteoblast or growth of stromal cells; Do not need second operation, and can make full use of the refresh function of osseous tissue itself, to reach bore regenerating effect fast.
Summary of the invention
Main purpose of the present invention is to provide a kind of pharmaceutical Biodegradable pottery, can be used as the skeleton (scaffolds) of bone cells, be fit to the growth of osteoblast or marrow stromal cell, have osseous tissue guiding generation (osteoconduction) simultaneously concurrently and induce generation (osteoinduction) ability, can be made into different shapes and size to be applied to the damaged regeneration repairing of various bones with osseous tissue.
Another object of the present invention is to provide a kind of manufacture method of pharmaceutical Biodegradable pottery, make to be connected to a suitable organic molecule on this pottery, can be used as a good conducting system.
Another purpose of the present invention is to provide a kind of conducting system of Biodegradable, this conducting system is applicable to the regeneration or the reparation of osseous tissue, make somatomedin or bone growth inducible factor in the osseous tissue, and the medicine used of bone treatment can conduct to growth place of osteoblast or marrow stromal cell, or osseous tissue place to be repaired.
Another purpose of the present invention is to provide the method for a kind of bone tissue reparation, and bone tissue's prosthetic device of Biodegradable, does not need second operation, and the regenerative power that makes full use of osseous tissue itself reaches rapidly effectively bore regenerating and repairing effect.
For achieving the above object, pharmaceutical Biodegradable pottery provided by the invention, it comprises the secondary calcium phosphate that a surface is modified through organic molecule, and wherein this organic molecule is hexa-methylene two isocyanic acids.
Described pharmaceutical pottery, wherein this organic molecule with the covalent grafting to this secondary calcium phosphate.
The method of the above-mentioned pharmaceutical Biodegradable pottery of preparation provided by the invention comprises following steps:
(A) provide 5 to 20g heavy secondary calcium phosphate powder, the about 0.1 μ m of this powder diameter;
(B) this secondary calcium phosphate powder is dissolved in the anhydrous organic solvent, stir about is 1 hour under anhydrous compression ring border; And
(C) add hexa-methylene two isocyanic acids of 3-12ml, and reacted 1-6 hour under in anhydrous compression ring border, temperature of reaction is 20-70 ℃.
Described preparation method, the wherein at least a group that forms by dimethyl formamide, dimethyl sulfoxide (DMSO), chlorocarbon that is selected from of the organic solvent of this step (B).
Described preparation method, wherein the temperature of reaction of this step (C) is between 40-60 ℃, and recommended temperature is 50 ℃.
Described preparation method, wherein this step (C) comprises a catalytic reagent is added in this reaction.
Described preparation method, wherein at least a this catalyzer is two-dodecane butyl tin.
The conducting system of Biodegradable provided by the invention comprises the secondary calcium phosphate that a surface is modified through organic molecule, and wherein this organic molecule is hexa-methylene two isocyanic acids.
Described conducting system, wherein this conducting system is used for the regeneration or the reparation of osseous tissue.
Described conducting system, wherein this conducting system is used to conduct the somatomedin or the bone growth inducible factor of osseous tissue itself, and/or conducts the medicine that bone treatment is used.
Described conducting system, wherein this medicine is somatomedin or bone growth inducible factor.
Described conducting system, wherein this medicine be with the covalent grafting to this secondary calcium phosphate.
Bone tissue's prosthetic device of Biodegradable provided by the invention, it comprises the secondary calcium phosphate that the surface is modified through organic molecule, and wherein this organic molecule is hexa-methylene two isocyanic acids.
Described bone tissue prosthetic device, wherein this organic molecule be with the covalent grafting to this secondary calcium phosphate.
The method that bone tissue provided by the invention repairs comprises the secondary calcium phosphate throwing that the surface is modified through organic molecule and gives bone tissue place to be repaired, and wherein this organic molecule is hexa-methylene two isocyanic acids.
Described restorative procedure, wherein this secondary calcium phosphate is a Biodegradable.
Described restorative procedure, wherein this organic molecule be with the covalent grafting to this secondary calcium phosphate.
Description of drawings
For more understanding technology contents of the present invention, preferred embodiment and accompanying drawings are as follows especially exemplified by counting:
Fig. 1 is the thermogravimetric analysis (TGA) and heating differential analysis (DTA) collection of illustrative plates of secondary calcium phosphate (CHP).
Fig. 2 is the thermogravimetric analysis (TGA) and heating differential analysis (DTA) collection of illustrative plates of the modified secondary calcium phosphate (MCHP) in the present invention surface.
Fig. 3 is thermogravimetric analysis (TGA) collection of illustrative plates of the prepared surperficial modified secondary calcium phosphate (MCHP) of various embodiments of the present invention.
Fig. 4 is heating differential analysis (DTA) collection of illustrative plates of the prepared surperficial modified secondary calcium phosphate (MCHP) of various embodiments of the present invention.
Fig. 5 is the prepared surperficial modified secondary calcium phosphate (MCHP) of the present invention
31The P-NMR collection of illustrative plates.
Fig. 6 is the prepared surperficial modified secondary calcium phosphate (MCHP) of the present invention
13The C-NMR collection of illustrative plates.
Fig. 6 a is pure HMDI's
13The C-NMR collection of illustrative plates.
Fig. 6 b is (embodiment 4) prepared MCHP under 50 ℃
13The C-NMR collection of illustrative plates.
Fig. 6 c is (embodiment 5) prepared MCHP under 60 ℃
13The C-NMR collection of illustrative plates.
Fig. 7 is that the prepared surperficial modified secondary calcium phosphate (MCHP) of the present invention is implanted the newborn situation of osseous tissue behind prominent (condyle) position of rabbit condyle shape.
Embodiment
As previously mentioned, bone tissue repairs three big key elements: skeleton (scaffold), cell and somatomedin (growth factors).Skeleton provides the position of attached outstanding hyperplasia of cell and differentiation, keeps organizer's Stability Analysis of Structures simultaneously.(hydroxyapatite HA), is fit to the osteoblast growth of being turned out by outer periosteum or medullary space cell to be applied to mostly be calcic pottery, especially porousness hydroxyapatite in the organizational project at present.In addition, the porousness hydroxyapatite is a Biodegradable, quite is suitable for the skeleton as osseous tissue.So, described in background of invention, only use the porousness hydroxyapatite, can only have the osseous tissue guiding and generate (osteoconduction) ability, induce generation (osteoinduction) ability and can't possess osseous tissue, do not have and go to make osteoblast to receive somatomedin and further differentiation.Therefore, basic phosphatic rock surface, porousness footpath must connect organic group again, makes it become a good somatomedin conducting system.Generally speaking, have dual mode can utilize organic molecule to modify the porousness hydroxyapatite surface, one of method commonly used is the surface adsorption mode, utilizes the physical property reactive force that organic molecule is adsorbed on the porousness hydroxyapatite surface; Right this kind magnetism is not strong, and this organic group is easy to be washed away under physiological environment down, and loses conduction.Another kind of mode then is to combine with the OH base of this hydroxyapatite by this organic group to form covalent linkage.
The present invention utilizes second kind of combination, utilizes special organic group to combine with the OH base of hydroxyapatite and forms covalent linkage.The present invention utilizes hexa-methylene two isocyanic acids, and (Hexamethylene diisocyanate, HMDI) the CN base on combines with the OH base of hydroxyapatite and forms covalent linkage.Its preparation method is that the secondary calcium phosphate powder with 5-20g is dissolved in the anhydrous organic solvent, and this organic solvent is preferably dimethyl formamide (DMF), sough (DMSO) in the dimethyl Asia or chlorocarbon (CC); The particle diameter of this secondary calcium phosphate powder is preferably about 0.1 μ m.Afterwards under anhydrous compression ring border, under nitrogen or inert gas environment, stir about 1 hour.Treat that this secondary calcium phosphate powder is dissolved in this organic solvent fully, and hexa-methylene two isocyanic acids that adding 5-20g is heavy (Hexamethylene diisocyanate, HMDI), and under anhydrous compression ring border, under nitrogen or inert gas environment, reacted 1-10 hour, be preferably 4 hours; Temperature of reaction is 20-70 ℃, is preferably 60 ℃, is more preferred from 50 ℃.Can optionally add suitable catalyzer in the reaction, this catalyzer is preferably two-(dodecane butyl tin) (dibutylin dilaurate).Just can get the surperficial secondary calcium phosphate that modification is arranged this moment, this secondary calcium phosphate powder filter gone out, and clean to remove the many bodies of unnecessary HMDI-with DMF.This surface there is the secondary calcium phosphate of modification clean three times, removes remaining DMF with acetone, and dry.
Be connected to HMDI on this secondary calcium phosphate surface, somatomedin in the osseous tissue or inducible factor can be conducted to via the HMDI group to paste on the osteoblast that grows in this secondary calcium phosphate surface: therefore, another viewpoint of the present invention is a kind of conducting system of Biodegradable, comprises a secondary calcium phosphate of should the surface modifying through HMDI.This conducting system is applicable to the regeneration or the reparation of osseous tissue, and can be used for conducting the somatomedin or the bone growth inducible factor of osseous tissue itself, or being used to conduct the bone treatment medicine that adds, this medicine is preferably somatomedin (growth factor) or bone growth inducible factor.
Because this secondary calcium phosphate is originally as a good medical stupalith, the surface just becomes a good conducting system after HMDI modifies; Therefore another viewpoint of the present invention is for providing a kind of bone tissue's prosthetic device of Biodegradable, and it comprises the secondary calcium phosphate that above-mentioned surface is modified through HMDI.Another viewpoint of the present invention comprises the secondary calcium phosphate throwing that surperficial HMDI is modified and gives bone tissue place to be repaired in the method that provides a kind of bone tissue to repair.
Be noted that following is embodiment only, but not is limited to embodiment.For example this does not break away from basic framework of the present invention, all should be the interest field that this patent is advocated, and should be as the criterion with patent claim.
A. prepare and embodiment
Material is prepared
(Hexamethylene diisocyanate, HMDI) available from Aldrich, being directly used in need not be through being further purified in the experiment for hexa-methylene two isocyanic acids.Secondary calcium phosphate (CaHPO
4) preparation be with dicalcium phosphate dihydrate (CaHPO
4.2H
2O) heated 8 hours down in 200 ℃, and identify with FTIR and X-ray refraction collection of illustrative plates earlier.Dimethyl formamide (DMF) is to deposit to distill the mode purifying and to add 4 dust molecular sieves.Two-dodecane butyl tin (dibutylin dilaurate) must directly not used by purifying available from Acros.
With median size is the dry CaHPO of 12.0 grams of 0.1 μ m
4Powder, 150 milliliters of DMF and 0.12 milliliter of two-dodecane butyl tin (dibutylin dilaurate) are inserted in 250 ml flasks; In this system, two-dodecane butyl tin is as catalyzer.Stirred 1 hour down in nitrogen environment.Add 6 milliliters of HMDI afterwards,, just can get secondary calcium phosphate (MCHP) precipitation of surface modification in 20 ℃, the following sustained reaction of nitrogen environment 4 hours.This MCHP precipitation powder is filtered out, and clean three times to remove the few body of unnecessary HMDI-with DMF.Clean three times with acetone again after the MCHP, remove remaining DMF, and dry.
Reaction process is roughly as embodiment 1, and the temperature of reaction that difference is to add behind the HMDI is as follows respectively:
| Embodiment | Temperature of |
| Embodiment | |
| 2 | 30 |
| Embodiment |
| 3 | 40 |
| Embodiment | |
| 4 | 50 |
| Embodiment | |
| 5 | 60 |
| Embodiment | |
| 6 | 70℃ |
B. property analysis
Analyze example 1 thermomechanical analysis
(thermal gravimetric analysis, TGA) (Differential thermal analysis, DTA) as heat analysis data, surveying instrument is SDT2960 (a TA instrument company) with heating differential analysis with thermogravimetric analysis in this experiment.In this experiment, analysis temperature is by room temperature to 600 ℃, and temperature rise rate is 20 ℃/min.CHP or MCHP are placed in the aluminium crucible, and add α-Al of 10 milligrams
2O
3, as the reference material.The quality that the HMDI amount hypothesis of grafting to the CHP is equal in the heat-processed to be lost, and represent with the weight percent with respect to total powder weight.The results are shown in Fig. 1 and Fig. 2.
Please refer to Fig. 1, be thermogravimetric analysis (TGA) and heating differential analysis (DTA) collection of illustrative plates of secondary calcium phosphate (CHP).Curve a among Fig. 1 (heating differential analysis, DTA) the heat absorption spike of demonstration CHP comes across 455.8 ℃, and this moment, CHP can convert Ca to
2P
2O
7(thermogravimetric analysis TGA) is presented at tangible mass loss is arranged between 445-482 ℃, for CHP can convert Ca to curve b among Fig. 1
2P
2O
7The water molecules that is scattered and disappeared.
Please refer to Fig. 2, for the thermogravimetric amount (TGA) of the modified secondary calcium phosphate (MCHP) in the present invention surface is analyzed and heating differential analysis (DTA) collection of illustrative plates.(heating differential analysis DTA) shows that MCHP has two heat absorption spikes, comes across 422.2 ℃ and 294.6 ℃ respectively to curve a among Fig. 2; Compare the back with Fig. 1 curve a and find, cause owing to CHP itself changes that in the spike of 422.2 ℃ of appearance 294.6 ℃ spike then is because HMDI burns caused.(thermogravimetric analysis TGA) shows two sections mass losses to curve b among Fig. 2, and b compares as can be known with Fig. 1 curve, and the mass loss of back segment is that CHP itself promptly has, and the mass loss of leading portion then is because the weight that the HMDI burning is lost.
From the above, the heating differential analysis of MCHP has two heat absorption spikes and occurs, and thermogravimetric analysis also has two constant intervals; And caused variation comes across first heat absorption spike and first constant interval because HDMI burns.Because we suppose the quality that the HMDI amount of grafting to the CHP is equal in the heat-processed to be lost, and therefore, cause that by the HMDI burning quality (difference of first constant interval) of being lost is bigger, the expression per-cent that HDMI connected is higher.
Please refer to Fig. 3, be thermogravimetric analysis (TGA) collection of illustrative plates of the prepared surperficial modified secondary calcium phosphate (MCHP) of various embodiments of the present invention.Show on the figure that all curves all occur two sections and change between song, meaning i.e. all embodiment all can effectively be prepared the MCHP that the surface is connected to HMDI.By can finding among Fig. 3, the prepared MCHP that goes out under the differing temps, its surperficial HMDI content is also inequality, and is wherein the highest with the contained HMDI amount of 60 ℃ of MCHP that prepare, and reaches 18.1wt%.Same result also is shown in Fig. 4, and Fig. 4 is heating differential analysis (DTA) collection of illustrative plates of the prepared surperficial modified secondary calcium phosphate (MCHP) of various embodiments of the present invention.
From the above, can effectively prepare the secondary calcium phosphate (MCHP) that the surface is modified through HMDI according to the inventive method.
2, NMR analyzes
The surperficial bond situation of MCHP be with
31P-NMR collection of illustrative plates (Fig. 5) with
13C-NMR collection of illustrative plates (Fig. 6) is analyzed.By
31P-NMR collection of illustrative plates (Fig. 5) as can be known, the phosphorus atom on CHP surface and the carbon atom on the HMDI form covalent linkage by Sauerstoffatom, that is the OH of CHP surface phosphoric acid root base can carry out chemical reaction and form covalent linkage with the CN base of HMDI.
Fig. 6's
13The C-NMR collection of illustrative plates be illustrated under 50 ℃ (embodiment 4) with 60 ℃ under (embodiment 5) prepared MCHP, the bond situation of its surperficial HMDI molecule and CHP.Fig. 6 a is pure HMDI's
13C-NMR collection of illustrative plates, Fig. 6 b are that temperature of reaction is 50 ℃ (embodiment 4) prepared MCHP's
13C-NMR collection of illustrative plates, Fig. 6 c temperature of reaction are 60 ℃ (embodiment 5) prepared MCHP's
13The C-NMR collection of illustrative plates.Fig. 6 display result confirms that as Fig. 5 the OH base of CHP surface phosphoric acid root can carry out chemical reaction and form covalent linkage with the CN base of HMDI; And compared by Fig. 6 b and Fig. 6 c, when temperature of reaction was 60 ℃, its surperficial HMDI molecule may continue to form bond with the HMDI molecule; Therefore, Zui Jia situation is that this temperature of reaction is maintained at 50 ℃.
As from the foregoing, the secondary calcium phosphate (MCHP) that surface of the present invention is modified through HMDI, its surperficial HMDI is connected with covalent and CHP, and binding ability and joint efficiency are all fairly good.CHP itself is tool Biodegradable and Bioabsorbable, after connecting organic molecule HMDI, just become the bone pottery of the good transport properties of a tool, this HMDI molecule can effectively transmit SGF, makes MCHP have osseous tissue guiding generation (osteoconduction) simultaneously concurrently and induces generation (osteoinduction) ability with osseous tissue.This specific character makes MCHP not only can be used as suitable osteoblast or the long skeleton (scaffolds) of marrow stromal cell, HMDI molecule on it more can effectively transmit SGF to herein, impels further differentiation and development osteogenic tissue of these precursor cells.
Application examples
To implant the defective of prominent (condyle) position diameter 6mm of rabbit condyle shape by the prepared material of embodiment 4, two week the back find that former defective is replaced by freshman bone tissue, repair fully, as shown in Figure 7.
In sum, medicinal bio-decomposable ceramics of the present invention has the tool Biodegradable, does not need second operation to take out after the implantation; And its granular size can not stopped up the marrow space, quite is fit to osteoblast or growth of stromal cells. In addition, its surface has the HMDI molecule, can be used as a good transmission system, but makes the required factor effective communication of bone growth to the Growth of Cells place; And then make MCHP have simultaneously bone tissue guiding concurrently to generate (osteoconduction) and induce generation (osteoinduction) ability with bone tissue. Through experiment confirm, medicinal bio-decomposable ceramics of the present invention can effectively help generation and the reparation of bone really. Characteristic according to this, medicinal bio-decomposable ceramics of the present invention more can further be applied as the method that a kind of skeletal tissue repairs, and a kind of skeletal tissue's prosthetic device of Biodegradable, do not need second operation to take out, and take full advantage of the power of regeneration of bone tissue itself, reach rapidly effectively bore regenerating and repairing effect.
Claims (13)
1, a kind of pharmaceutical Biodegradable pottery comprises a surface through the secondary calcium phosphate with covalent grafting hexa-methylene two isocyanic acids.
2, a kind of manufacture method of pharmaceutical Biodegradable pottery comprises following steps:
(A) provide 5 to 20g heavy secondary calcium phosphate powder, the about 0.1 μ m of this powder diameter;
(B) this secondary calcium phosphate powder is dissolved in the anhydrous organic solvent, stir about is 1 hour under anhydrous compression ring border; And
(C) add hexa-methylene two isocyanic acids of 3-12ml, and reacted 1-6 hour under in anhydrous compression ring border, temperature of reaction is 20-70 ℃.
3, method as claimed in claim 2 is characterized in that, wherein at least a group that is made up of dimethyl formamide, dimethyl sulfoxide (DMSO), chlorocarbon that is selected from of the organic solvent of this step (B).
4, method as claimed in claim 2 is characterized in that, wherein the temperature of reaction of this step (C) is between 40-60 ℃.
5, method as claimed in claim 2 is characterized in that, wherein the temperature of reaction of this step (C) is 50 ℃.
6, method as claimed in claim 2 is characterized in that, wherein this step (C) comprises a catalytic reagent is added in this reaction.
7, method as claimed in claim 6 is characterized in that, wherein at least a this catalyzer is two-dodecane butyl tin.
8, a kind of conducting system of Biodegradable comprises a surface through the secondary calcium phosphate with covalent grafting hexa-methylene two isocyanic acids.
9, conducting system as claimed in claim 8 is characterized in that, wherein this conducting system is used for the regeneration or the reparation of osseous tissue.
10, conducting system as claimed in claim 8 is characterized in that, wherein this conducting system is used to conduct the somatomedin or the bone growth inducible factor of osseous tissue itself, and/or conducts the medicine that bone treatment is used.
11, conducting system as claimed in claim 10 is characterized in that, wherein this medicine is somatomedin or bone growth inducible factor.
12, conducting system as claimed in claim 11 is characterized in that, wherein this medicine be with the covalent grafting to this secondary calcium phosphate.
13, a kind of bone tissue's prosthetic device of Biodegradable, it comprises the surface through the secondary calcium phosphate with covalent grafting hexa-methylene two isocyanic acids.
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| CN 03110229 CN1241871C (en) | 2003-04-07 | 2003-04-07 | Medicinal bio-decomposable ceramics |
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| CN 03110229 CN1241871C (en) | 2003-04-07 | 2003-04-07 | Medicinal bio-decomposable ceramics |
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| CN1241871C true CN1241871C (en) | 2006-02-15 |
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