CN104857559B - Bone repair product with degradable copolymer-calcium silicate composite bone repair materials serving as raw materials - Google Patents
Bone repair product with degradable copolymer-calcium silicate composite bone repair materials serving as raw materials Download PDFInfo
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- CN104857559B CN104857559B CN201510219762.5A CN201510219762A CN104857559B CN 104857559 B CN104857559 B CN 104857559B CN 201510219762 A CN201510219762 A CN 201510219762A CN 104857559 B CN104857559 B CN 104857559B
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Abstract
The invention discloses a bone repair product with degradable copolymer-calcium silicate composite bone repair materials serving as raw materials. The composite bone repair materials are composed of degradable lactic acid-basic amino acid copolymers and calcium silicate. The calcium silicate occupies 25% to 40% of the total mass of the bone repair materials, and the lactic acid-basic amino acid copolymers is formed by polymerization of L-lactic acid and at least one alpha-basic amino acid, wherein the basic amino acid is 5% to 30% of the total molar weight of the copolymers. The bone repair product is degradable in bodies and capable of providing calcium and silicon ions for bone tissues, high in biological activity; apparent advantages are provided in aspects of promotion of collagen synthesis, cell proliferation and differentiation and the like; degradation products has no obvious effect on surroundings.
Description
The application is the applying date: January 25, application number: 201510034938.x, invention in 2015
Title: the division of the patent application of biodegradable block copolymer-calcium silicates composite bone repairing material and preparation method
Application.
Technical field
The present invention relates to a kind of Bone Defect Repari product for bone tissue defect repair, it is especially degradable
Copolymer-calcium silicates composite bone repairing material is the Bone Defect Repari product of raw material.
Background technology
In bone tissue agglutination, in the presence of degradable biological material water and enzyme in body fluid, can
Formation organizes and moves back into (growth) material the desired tissue reproduced state of (degraded or absorb) to be subject to
Extensive concern.For degradable high polymer material, including such as PLA, lactic acid-acetate multipolymer,
The artificial synthesized degradable high polymer material such as polyaminoacid, polycaprolactone, polyvinyl alcohol, and as shell gathers
The natural degradable macromolecule such as sugar, chitin, protein, collagen two big class.These macromolecular materials
All degradable, and degradation speed can be by the realization such as Molecular regulator amount, crystal habit.But as bone
The repair materials used time, have that mechanical strength is poor, degradation property is not good more these macromolecular materials, exist and exempt from
The shortcomings of epidemic disease rejection.And the macromolecular material of single composition is not provided that promotion when repairing bone tissue
The calcium ion of skeletonization and phosphate anion, lack good osteogenic activity.
For this reason, degradable high polymer material is degradable multiple with what the calcium microcosmic salt with biologically active was composited
Condensation material, is the hot fields of current bone renovating material.As PLA-calcium phosphate, polylactic acid-glycolic base phosphorus
Grey stone composite material, polyaminoacid-calcium sulfate, polyaminoacid-calcium phosphate, polyaminoacid-hydroxy-apatite
Stone, polyaminoacid-calcium silicates, and collagen-hydroxyapatite composite etc., wherein only collagen-hydroxyl
Apatite composite material has been used for clinic at present.In this kind of material, it is anti-that collagen may produce immunological rejection
Should, and the mechanical property of its composite is not good；PLA-calcium salt composite produces in degradation process
Raw acid lactic acid, easily causes aseptic inflammation；Polyaminoacid in polyaminoacid-calcium salt composite
Solubility property and processability still not ideal enough.
In the macromolecule phase in degradable composite bone repairing material, lactic acid can be by the mode fermented
Obtain, its source is unrestricted, and when artificial synthesized, its composition, purity are all controlled.After lactic acid copolymerization
The PLA being formed is a kind of macromolecular material with good degradation property, and anti-in its product is adhered
Film, Absorbable plate and plate etc. are in clinical a large amount of uses.But with clinical practice quantity increase and when
Between extend, the shortcoming of PLA also begins to manifest, and the degradation speed of such as l- lactic acid copolymer is too fast, and
After implanting, its catabolite lactic acid easily causes the inflammatory reaction of local, so that application is subject to greatly
Limit.Thus, more preferably degradable composite material becomes an important problem for research.
Content of the invention
For above-mentioned situation, the invention provides a kind of bone of the degradable composite bone repairing material of new model
Repair reuse artifacts, be especially a kind of biodegradable block copolymer-calcium silicates composite bone repairing material be raw material
Bone Defect Repari product.
Biodegradable block copolymer of the present invention-calcium silicates composite bone repairing material is the Bone Defect Repari product of raw material,
Wherein, biodegradable block copolymer-calcium silicates composite bone repairing material is common by degradable lactic acid-basic amino acid
Polymers is combined composition with calcium silicates, and wherein calcium silicates is the 25～40% of described bone renovating material gross mass,
Lactic acid-basic amine group acid copolymer is polymerized with least one α-basic amino acid by l- lactic acid, wherein
Basic amino acid is the 5～30% of copolymer integral molar quantity.
Wherein, in described biodegradable block copolymer-calcium silicates composite bone repairing material, basic amino acid is bad
At least one in propylhomoserin, histidine, arginine.
Wherein, in described biodegradable block copolymer-calcium silicates composite bone repairing material, lysine is copolymer
The 5～30% of integral molar quantity, histidine is the 5～20% of copolymer integral molar quantity, and arginine is copolymer
The 5～10% of integral molar quantity.
Wherein, in described biodegradable block copolymer-calcium silicates composite bone repairing material, basic amino acid is common
The 15～30% of polymers integral molar quantity.
Wherein, described calcium silicates is the 25～40% of described bone renovating material gross mass.
Wherein, what described biodegradable block copolymer-calcium silicates composite bone repairing material was processed into meets clinic
Using the Bone Defect Repari product including bar, block, bar form needing.
Biodegradable block copolymer of the present invention-calcium silicates composite bone repairing material, research is it has been proved that in vivo
Calcium ion after release is conducive to skeletonization, and can form biologically active interface between material and tissue.Mesh
Front for bioactive ingredients used in bone tissue composite, generally use hydroxyapatite
And tricalcium phosphate, also include calcium sulfate, calcium monohydrogen phosphate and part organic calcium salt etc..Ratio in recent years
Relatively research finds, when siliceous calcium salt uses as bone renovating material, can have with respect to aforementioned not siliceous salt
There is higher biologically active, element silicon therein is in terms of promoting collage synthesis and promoting cell proliferation and differentiation
There is obvious effect, and silicon, calcium simultaneously in the presence of, it becomes apparent to cell and tissue growth aspect
Better than single calcium microcosmic salt.Based on this, in composite bone repairing material of the present invention, employ calcium silicates and make
For inorganic active composition.Experiment display, is described bone renovating material gross mass beyond above-mentioned calcium silicates
10～50% scope, higher silicic acid calcium content can make composite material exhibits go out more obvious fragility, and
It is unfavorable for follow-up extrusion molding and injection molding shaping；And the calcium silicates crossing low content then can affect composite
Biologically active.Wherein, the more preferable ratio of calcium silicates can be chosen as bone renovating material gross mass
25～40%, be conducive to making composite preferably take into account good biologically active and good toughness.
Because the above-mentioned biodegradable block copolymer of the present invention-calcium silicates composite bone repairing material can be dropped in vivo
Solution, the basic amino acid therefore described in material, the lysine that preferably can absorb for human body,
At least one in histidine, arginine.
Using basic amino acid in composite bone repairing material of the present invention, except adjustable and change copolymer
Degradation speed, particularly can make the acid of produced basic amino acid and lactic acid after material degradation in vivo
Property mutually neutralize, with reduce catabolite to tissue stimulation.Due to different basic amino acids
Ph value has differences, taking above-mentioned preferred three kinds of basic amino acids as a example, the ph value of arginine itself
Highest, is highly basic acidic amino acid, and the ph value of histidine and lysine is then relatively low, therefore for reaching
Preferably neutralize the acidity of lactic acid, the actually used amount of different basic amino acids can be according to basic amine group used
The alkalescence height of acid appropriately adjusts.For example, for three kinds of above-mentioned basic amino acids, described relies
Propylhomoserin is preferably the 5～30% of copolymer integral molar quantity, and histidine is preferably copolymer integral molar quantity
5～20%, arginine is then preferably the 5～10% of copolymer integral molar quantity, can obtain comparatively ideal common
Polymers.
Test display, the total amount of copolymer neutral and alkali amino acid too low it is difficult to the property of copolymer can be changed
Can, and the molecular weight and molecular weight of copolymer during too high levels, can be led to, and the intermolecular hydrogen bond of easy formation, no
Degraded beneficial to copolymer.In therefore above-mentioned copolymer, more preferable basic amino acid ratio can be chosen as altogether
The 15～25% of polymers integral molar quantity.
With the above-mentioned biodegradable block copolymer of the present invention-calcium silicates composite bone repairing material as raw material, through routine
Extrusion molding or the processing mode such as injection, you can be made for corresponding Bone Defect Repari product.For example, can process
Become meets the Bone Defect Repari product facing using needs including bar, block, bar form.
As above-mentioned, biodegradable block copolymer of the present invention-calcium silicates composite bone repairing material is the Bone Defect Repari of raw material
With product, can degrade in vivo, catabolite not only has no significant effect to surrounding environment, and can be
Bone tissue provides calcium, the silicon ion with higher biologically active, is promoting collage synthesis, cell proliferation
The aspects such as differentiation have more more obvious advantage than currently reported similar Bone Defect Repari product, have greatly
It is worth and development, application prospect.
Specific embodiment below in conjunction with drawings and Examples is made further to the above of the present invention again
Detailed description.But this scope being interpreted as the above-mentioned theme of the present invention should not be only limitted to Examples below.
Without departing from the idea case in the present invention described above, according to ordinary skill knowledge and customary means
The various replacements made or change, all should be included within the scope of the invention.
Brief description
Fig. 1 is the comparing result of material of the present invention and control material cell proliferation test.
Fig. 2 is the comparing result of material of the present invention and the test of control material cell differentiation.
Fig. 3 artificial neural plate.
Fig. 4 cervical vertebral fusion cage.
Fig. 5 centrum product.
Specific embodiment
Embodiment 1
By 0.8 molar lactic acid, 0.1 mole of lysine, 0.05 mole of histidine, 0.05 mole of arginine,
And the catalyst stannous chloride of reactant gross mass 0.4% adds in reactor, stir, keep pressure
Power 0.1mpa, is warming up to 120 DEG C ± 5 DEG C, is dehydrated 2 hours；It is warming up to 140 DEG C ± 5 DEG C, before reaction
Keep pressure 0.01mpa in 3 hours, keep pressure 5000pa afterwards and continue to react 12 hours；It
Afterwards, it is warming up to 180 DEG C -200 DEG C, pressure 70pa, reacts 8 hours；It is subsequently adding calcium silicates, equally
Condition continues reaction 2 hours, is cooled to room temperature and obtains composite.
Materials processing is become diameter 10mm, the disk of height 2mm carries out Degrading experiment.With phosphoric acid buffer
Liquid, as soak, disk is soaked, sample quality: soak volume is 1g:30ml.Soak 12
Zhou Hou, material weight-loss ratio reaches 58%, and soak ph fluctuates in the range of 6.9-7.3.
Embodiment 2
By 0.7 molar lactic acid, 0.1 mole of lysine, 0.1 mole of histidine, 0.1 mole of arginine and anti-
The catalyst stannous chloride answering thing gross mass 0.4% adds in reactor, stirs, keeps pressure
0.1mpa, is warming up to 120 DEG C ± 5 DEG C, is dehydrated 2 hours；It is warming up to 140 DEG C ± 5 DEG C, front the 3 of reaction
Keep pressure 0.01mpa in hour, keep pressure 5000pa afterwards and continue to react 12 hours；It
Afterwards, it is warming up to 180 DEG C -200 DEG C, pressure 70pa, reacts 8 hours；It is subsequently adding calcium silicates, equally
Condition continues reaction 2 hours, is cooled to room temperature and obtains composite.
Degrading experiment condition is with example 1.After soaking 12 weeks, material weight-loss ratio reaches 48%, soak
Ph fluctuates in the range of 6.9-7.5.
Embodiment 3
By 0.95 molar lactic acid, 0.05 mole of arginine, and the catalyst chlorine of reactant gross mass 0.4%
Change stannous to add in reactor, stir, keep pressure 0.1mpa, be warming up to 120 DEG C ± 5 DEG C,
Dehydration 2 hours；It is warming up to 140 DEG C ± 5 DEG C, in first 3 hours of reaction, keep pressure 0.01mpa, it
Keep pressure 5000pa afterwards and continue to react 12 hours；Afterwards, it is warming up to 180 DEG C -200 DEG C, pressure
70pa, reacts 8 hours；It is subsequently adding calcium silicates, similarity condition continues reaction 2 hours, is cooled to room
Temperature obtains composite.
Degrading experiment condition is with example 1.After soaking 12 weeks, material weight-loss ratio reaches 65%, soak
Ph fluctuates in the range of 7.1-7.7.
Embodiment 4
By 0.7 molar lactic acid, 0.3 mole of lysine, and the catalyst chlorination of reactant gross mass 0.3%
Stannous add in reactor, stir, and keep pressure 0.1mpa, are warming up to 120 DEG C ± 5 DEG C, take off
Water 2 hours；It is warming up to 140 DEG C ± 5 DEG C, keep pressure 0.01mpa in first 3 hours of reaction, afterwards
Keep pressure 5000pa and continue to react 12 hours；Afterwards, it is warming up to 180 DEG C -200 DEG C, pressure
70pa, reacts 8 hours；It is subsequently adding calcium silicates, similarity condition continues reaction 2 hours, is cooled to room
Temperature obtains composite.
Degrading experiment condition is with example 1.After soaking 12 weeks, material weight-loss ratio reaches 45%, soak
Ph fluctuates in the range of 7.0-7.4.
Embodiment 5
By 0.95 molar lactic acid, 0.05 mole of lysine, and the catalyst chlorine of reactant gross mass 0.6%
Change stannous to add in reactor, stir, keep pressure 0.1mpa, be warming up to 120 DEG C ± 5 DEG C,
Dehydration 2 hours；It is warming up to 140 DEG C ± 5 DEG C, in first 3 hours of reaction, keep pressure 0.01mpa, it
Keep pressure 5000pa afterwards and continue to react 7 hours；Afterwards, it is warming up to 180 DEG C -200 DEG C, pressure
70pa, reacts 6 hours；It is subsequently adding calcium silicates, similarity condition continues reaction 2 hours, is cooled to room
Temperature obtains composite.
Degrading experiment condition is with example 1.After soaking 12 weeks, material weight-loss ratio reaches 85%, soak
Ph fluctuates in the range of 6.2-6.9.
Embodiment 6
By 0.95 molar lactic acid, 0.5 mole of lysine, and the catalyst chlorination of reactant gross mass 0.6%
Stannous add in reactor, stir, and keep pressure 0.1mpa, are warming up to 120 DEG C ± 5 DEG C, take off
Water 2 hours；It is warming up to 140 DEG C ± 5 DEG C, keep pressure 0.01mpa in first 3 hours of reaction, afterwards
Keep pressure 5000pa and continue to react 12 hours；Afterwards, it is warming up to 180 DEG C -200 DEG C, pressure
70pa, reacts 8 hours；It is subsequently adding calcium silicates, similarity condition continues reaction 2 hours, is cooled to room
Temperature obtains composite.
Degrading experiment condition is with example 1.After soaking 12 weeks, material weight-loss ratio reaches 35%, soak
Ph fluctuates in the range of 6.6-7.2.
Embodiment 7
The composite of Example 1～6 preparation, is added using conventional injection, hot pressing or general machine
The mode of work prepares the variously-shaped product required for clinic.
Injection is commonly used for preparing thickness of thin, erose product.To prepare Fig. 3 artificial neural plate it is
Example illustrates.It is first according to article shape processing mold, then mould is attached on injection machine, set
Product injection temperature, its scope is 140 DEG C -185 DEG C, sets injection pressure, its scope is 40-
90mpa.Carry out with this understanding being molded can get injection-molded item.
Hot-press method is to put in mould by composite powder, and then in certain temperature range, plasticizing is
Can get product.Taking prepare the cervical vertebral fusion cage as Fig. 4 as a example, composite powder is loaded mould
In, plastify 5-10 minute in the range of 170 DEG C ± 5 DEG C, after being cooled to room temperature, can get corresponding system
Product.
Machine-tooled method is that the block of the composite using synthesis passes through the side such as car, milling, plane, mill, brill
Formula prepares product.Centrum product shown in Fig. 5 can be prepared by machining mode.
Comparative example 1
(lactic acid-amino acid)/calcium silicates (la-aa/casio that embodiment 1 is obtained3) material (sample
Piece group), with (lactic acid-amino acid)/hydroxyapatite (la- being prepared with the same terms
Aa/ha) (control group), contrast has carried out cell proliferation test and cell differentiation test.Result is sent out
Existing, after culture 1,3,5,7 days, the result of the cell proliferation test of sample sets as shown in figure 1,
The result (alkaline phosphatase index) of cell differentiation test is as shown in Figure 2.The result of two tests is all aobvious
Show, the result of material sample group of the present invention is all significantly better than control group.In figure: * all represent sample sets and
The result of control group has significant difference.
Claims (9)
1. biodegradable block copolymer-calcium silicates composite bone repairing material is the Bone Defect Repari product of raw material,
Wherein, biodegradable block copolymer-calcium silicates composite bone repairing material is by degradable lactic acid-alkaline ammonia
Base acid copolymer and calcium silicates are combined composition, and wherein calcium silicates is described bone renovating material gross mass
25～40%, lactic acid-basic amine group acid copolymer is by l- lactic acid and at least one α-alkaline ammonia
Base acid is polymerized, and wherein basic amino acid is the 5～30% of copolymer integral molar quantity.
2. Bone Defect Repari product as claimed in claim 1, is characterized in that described degradable copolymerization
In thing-calcium silicates composite bone repairing material, basic amino acid is lysine, histidine, smart ammonia
At least one in acid.
3. Bone Defect Repari product as claimed in claim 2, is characterized in that described degradable copolymerization
In thing-calcium silicates composite bone repairing material, lysine is the 5～30% of copolymer integral molar quantity,
Histidine is the 5～20% of copolymer integral molar quantity, and arginine is copolymer integral molar quantity
5～10%.
4. the Bone Defect Repari product as described in one of claims 1 to 3, it is characterized in that described can
In degraded copolymer-calcium silicates composite bone repairing material, basic amino acid is copolymer total moles
The 15～30% of amount.
5. Bone Defect Repari product as claimed in claim 4, is characterized in that described degradable copolymerization
In thing-calcium silicates composite bone repairing material, calcium silicates is described bone renovating material gross mass
25～40%.
6. Bone Defect Repari product as claimed in claim 4, is characterized in that by described degradable
What copolymer-calcium silicates composite bone repairing material was processed into meets bar, the block of Clinical practice needs
Or the Bone Defect Repari product of bar form.
7. the Bone Defect Repari product as described in one of claims 1 to 3, it is characterized in that described can
In degraded copolymer-calcium silicates composite bone repairing material, calcium silicates is that described bone renovating material is total
The 25～40% of quality.
8. Bone Defect Repari product as claimed in claim 7, is characterized in that by described degradable
What copolymer-calcium silicates composite bone repairing material was processed into meets bar, the block of Clinical practice needs
Or the Bone Defect Repari product of bar form.
9. the Bone Defect Repari product as described in one of claims 1 to 3, is characterized in that by described
What biodegradable block copolymer-calcium silicates composite bone repairing material was processed into meets Clinical practice needs
The Bone Defect Repari product of bar, block or bar form.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510219762.5A CN104857559B (en) | 2015-01-25 | 2015-01-25 | Bone repair product with degradable copolymer-calcium silicate composite bone repair materials serving as raw materials |
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| CN201510034938.XA CN104524630A (en) | 2015-01-25 | 2015-01-25 | Degradable copolymer-calcium silicate composite bone repair material and preparation method thereof |
| CN201510219762.5A CN104857559B (en) | 2015-01-25 | 2015-01-25 | Bone repair product with degradable copolymer-calcium silicate composite bone repair materials serving as raw materials |
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| CN201510216660.8A Expired - Fee Related CN104841011B (en) | 2015-01-25 | 2015-01-25 | The preparation method of biodegradable block copolymer-calcium silicates composite bone repairing material |
| CN201510219762.5A Expired - Fee Related CN104857559B (en) | 2015-01-25 | 2015-01-25 | Bone repair product with degradable copolymer-calcium silicate composite bone repair materials serving as raw materials |
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| CN201510216660.8A Expired - Fee Related CN104841011B (en) | 2015-01-25 | 2015-01-25 | The preparation method of biodegradable block copolymer-calcium silicates composite bone repairing material |
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| CN104524630A (en) * | 2015-01-25 | 2015-04-22 | 宁波开发区中心医院 | Degradable copolymer-calcium silicate composite bone repair material and preparation method thereof |
| CN106620871A (en) * | 2017-01-09 | 2017-05-10 | 中国人民解放军第二军医大学第二附属医院 | Bone repairing product taking degradable copolymer-calcium silicate composite bone repairing material enhanced by hydroxyapatite whisker as raw material |
| CN106730024A (en) * | 2017-01-09 | 2017-05-31 | 中国人民解放军第二军医大学第二附属医院 | Hydroxyapatite crystal whisker strengthens biodegradable block copolymer calcium silicates composite bone repairing material |
| CN106880875A (en) * | 2017-01-09 | 2017-06-23 | 中国人民解放军第二军医大学第二附属医院 | Hydroxyapatite crystal whisker strengthens the preparation method of biodegradable block copolymer calcium silicates composite bone repairing material |
| CN109010908A (en) * | 2018-10-17 | 2018-12-18 | 广州润虹医药科技股份有限公司 | A kind of drug controlled-releasing function activity artificial bone and preparation method thereof |
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| CN100391418C (en) * | 2004-03-05 | 2008-06-04 | 中国科学院上海硅酸盐研究所 | Bioactive composite cytoskeleton made of degradable porous polyester/calcium silicate, prepn. method and use thereof |
| US8147860B2 (en) * | 2005-12-06 | 2012-04-03 | Etex Corporation | Porous calcium phosphate bone material |
| KR101041784B1 (en) * | 2009-06-26 | 2011-06-17 | (주)시지바이오 | Bone-repair composition |
| CN102824657B (en) * | 2011-07-29 | 2014-05-21 | 深圳先进技术研究院 | Bone restoration material and preparation method thereof |
| CN104524630A (en) * | 2015-01-25 | 2015-04-22 | 宁波开发区中心医院 | Degradable copolymer-calcium silicate composite bone repair material and preparation method thereof |
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| CN104857559A (en) | 2015-08-26 |
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Granted publication date: 20170118 Termination date: 20180125 |
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| CF01 | Termination of patent right due to non-payment of annual fee |