CN108553691A - Artificial bone renovating material of Injectable self-curable and preparation method thereof - Google Patents
Artificial bone renovating material of Injectable self-curable and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Abstract
The present invention relates to artificial bone renovating materials of Injectable self-curable and preparation method thereof.Preparation method includes：The preparation of biphasic calcium phosphate porous particle, the preparation of mineralized collagen porous calcium phosphate composite material and the mixture with half-H 2 O calcium sulphate.Artificial bone renovating material obtained has the property that：(a) mineralized collagen is evenly distributed on surface and the hole of biphasic calcium phosphate porous particle, and mineralized collagen is made equably to be combined with porous calcium phosphate, to have better biocompatibility；(b) there is porous structure, be not only advantageous to growth and the creeping substitution of bone tissue, also there is certain support strength；(c) anti-inflammatory therapy can be carried out as growth factor and the carrier of all kinds of antibiotic；(d) develop under X-ray, convenient for checking；(e) degradable, secondary pain caused by taking out is avoided, and degradation rate can be with new bone growth rate-matched；(f) can injectable in situ, and there is excellent self-curing performance.
Description
Technical field
The present invention relates to biomedical material technology more particularly to the artificial bone renovating material of Injectable self-curable and its
Preparation method.
Background technology
Bone tissue is maximum as human body while being also to be easiest to cause the histoorgan of defect, has every year millions of
Bone tissue defect patient need be treated surgically.It is lost by the bone object official caused by osteoporosis, wound, tumour, infection
Or tissue defect has become one of the problem of puzzlement human health life.Clinically generally go through the operation of bone collection reconstruction
Restore the shape and function of defect, bone collection has become the graft having the call for being only second to blood transfusion, Er Qieyou
Increased trend year by year.
Currently, the implantation material for the treatment of bone defect is broadly divided into autologous bone, allograph bone, bone- xenograft, artificial bone etc..Self
Bone collection is the most method of current Clinical practice, but it is cost " being cured the wound with wound " that it, which is a kind of sacrifice health position bone tissue,
Treatment means, the areas Hui Duigonggu cause new damage, and autologous bone limited source.Homogeneous allogenic bone or bone xenograft are most
Pipe overcomes the defect of autologous bone transplanting " limited source and secondary insult ", but deposits immunological rejection after the transfer, also deposits
In pathophorous potential danger.Various existing for autologous bone, allograph bone and bone xenograft to overcome the problems, such as, people exert always
Power wishes to prepare ideal artificial bone renovating material by manual method.
Artificial bone renovating material is mostly regular shape well prepared in advance, utilized when fill irregular shape it is insufficient or
Person's filling is incomplete, so needing a kind of artificial bone renovating material for capableing of self-curing, disclosure satisfy that filling of different shapes, and
And can one's own department or unit self-curing, ensure good filling.
When in treatment, some have the patient of infection, material used is not easy to load antibiotic, often goes out in clinical treatment
Now due to tumour or cyst excision, wound, infection, congenital disorders, operation, nonunion and the bone defect formed.These
The presence of defect causes lesion biomechanical environment to change, and function is useless to be used or cause to infect, and is caused to the life of patient bad
It influences.Therefore, people need to fill defect using bone substitute in the treatment, restore the shape of lesion, mechanical strength and
Function eliminates dead space, reduces postoperative infection.This material should have good biocompatibility and self-bone grafting ability, energy simultaneously
Enough have and the matched degradation speed of self bone uptake.
Traditional bone cement has higher intensity, but high fever is generated in process of setting, can lead to soft group of adjacent healthy
The damage knitted.For example PMMA bone cements are non-degradable material, cannot be formed and are chemically bonded with host bone tissue, in solidification process
The release of high fever output and methyl methacrylate monomer also damage tissue and cell in region.
Mineralized collagen is the bionic bone repair material with hierarchical structure of bionical nature bone extracellular matrix design,
Micro-structure and two aspect of ingredient are all similar to nature bone, there is good biocompatibility and self-bone grafting repair ability, are a kind of excellent
Good bone renovating material.
In patent application file before (application No. is 201210254608.8), we have developed it is a kind of utilize mine
Anti-infective mineralized collagen-calcium sulfate bone that change collagen, α-half-H 2 O calcium sulphate, vancomycin and calcium sulphate dihydrate are compounded into repairs material
Material has good syringeability, biocompatibility and self-curing performance, degradable, drug slow release, anti-infective, promotion
Sticking for osteoblast is sprawled.But the bone renovating material has the following problems：
(a) a kind of vancomycin this antibiotic can only be loaded, and the antibiotic that can not load other types is either grown
The factor；
(b) for the trouble of certain inflammation heavier (such as due to tumour or cyst excision, wound, the inflammation of infection initiation)
The immune response of person, bone defect position are more strong, have higher requirement to the biocompatibility of material at this time；
(c) α-half-H 2 O calcium sulphate, which has good biocompatibility especially, has good fluid syringeability, one's own department or unit from admittedly
The property changed and plasticity, but degradation speed is too fast, is completely absorbed within 1~3 month, and degradation rate and new bone growth rate are not
Match.
Have relevant research about application of the phosphoric acid class calcium salt in bone renovating material, such as application No. is
201210558900.9, have related record in the application documents such as 201310682213.2,201110130874.5.But inventor exists
It is found in research, the degradation time of calcium phosphate material is long or can not degrade.It is carried out when using calcium phosphate bone repair material
When treatment, the bone renovating material of part sufferer also needs to take out by performing the operation, and easily causes secondary injury to sufferer.
In view of this, we have developed a kind of novel Injectable self-curable bone renovating material and preparation method thereof.
Invention content
(1) technical problems to be solved
In view of the above technical problems, the present invention provides a kind of artificial bone renovating material of Injectable self-curable and its preparation sides
Method.
(2) technical solution
In order to solve the above technical problem, the present invention provides following technical solutions：
The preparation method of the artificial bone renovating material of Injectable self-curable, the preparation method include the following steps：
(1) preparation of biphasic calcium phosphate porous particle：It prepares component and includes the first calcium salt, polyvinyl alcohol and PMMA microsphere,
Mass ratio is (0.1~0.5):3:2, first calcium salt is by hydroxyapatite and beta-calcium phosphate according to 5:1~1:3 mass ratio
Composition, preparation method include：
(a) compound concentration is the poly-vinyl alcohol solution of 0.2~0.5g/mL；
(b) two-phase phosphate suspension is prepared；Hydroxyapatite and beta-calcium phosphate are added in PBS solution, formed outstanding
Turbid；
(c) poly-vinyl alcohol solution is added in the two-phase phosphate suspension, after stirring 0.5~1 hour, then is added
Enter PMMA microsphere, after stirring 0.5~1 hour, obtains sintering base fluid；
(d) the sintering base fluid is placed in agglomerating plant and is sintered, obtain agglomerated material；
The sintering includes such as the next stage：
First stage：Heating rate be 5~10 DEG C/min, target temperature be 400~800 DEG C, constant temperature time be 300~
350min；
Second stage：Heating rate be 5~10 DEG C/min, target temperature be 1000~1200 DEG C, constant temperature time be 180~
200min；
Phase III：Agglomerating plant is stopped heating, cooled to room temperature；
(e) agglomerated material is crushed；
(f) it sieves；
(2) preparation of mineralized collagen porous calcium phosphate composite material：Biphasic calcium phosphate porous particle is added to a concentration of 1
In the collagen acid solution of~5mg/mL, it is stirred 2~3 hours, is configured to the suspension of a concentration of 10~30wt%；
Continue stirred suspension, the solution of calcium ions is added dropwise, the addition of calcium ion is that every gram of collagen corresponds to addition calcium
0.01~0.15mol of ion；The molar ratio of the solution of dropwise addition phosphorus-containing acid ion, phosphate anion and calcium ion is Ca/P=
0.8~1.8；NaOH solution is added dropwise to mixed system pH to 7~8 in lasting stirring, and when pH reaches 5~6, mixed system starts
It precipitates, when pH reaches 7, white suspension occurs in mixed system；Gained mixed system is stood 24~96 hours, separation
Go out to precipitate and wash away foreign ion, be then freeze-dried, the mineralising that mineralized collagen content is 2~25wt% is obtained after grinding
Collagen porous calcium phosphate composite material；
(3) mixture：By mineralized collagen porous calcium phosphate composite material and α-sulfate hemihydrate calcium powder according to 7:3~2:8
Mass ratio mixes, and the artificial bone renovating material of Injectable self-curable is made through dry and sterilizing in mixture.
Preferably：In step (1), the PMMA microsphere uses grain size for any one of 50~800 microns or two
Kind；The preferably PMMA microsphere of 50~200 microns of grain size and the PMMA microsphere of 400~600 microns of grain size is according to 2:8~8:2 matter
Measure the mixture than composition.
Preferably：In step (1), prepare component in also include in step (b) in be added the second calcium salt, described second
Calcium salt is selected from type alpha tricalcium phosphate, dicalcium phosphate dihydrate, calcium monohydrogen phosphate, tetracalcium phosphate any one or more of, and dosage accounts for calcium salt
The 1~10% of gross mass.
Preferably：In step (2), the solvent used in the collagen acid solution is prepared in hydrochloric acid, citric acid, acetic acid
It is any.
Preferably：In step (3), the α-sulfate hemihydrate calcium powder is prepared as follows：
By calcium sulphate dihydrate, sodium citrate, aluminum sulfate and water according to 1:0.0025:0.0025:5.67 mass ratio adds to
In reaction vessel, stirring is then sealed and opens, in 120 DEG C of conditioned response 6 hours；Reaction solution is taken out while hot after completion of the reaction
It filters, rinses filter cake 3~5 times with deionization boiling water after suction filtration, it is small that filter cake is then put into 100 DEG C of dryings 12~24 in drying box
When, half-H 2 O calcium sulphate is made；
It is sieved by half-H 2 O calcium sulphate grind into powder, then with 100 mesh sieve, the powder of sieving is α-sulfate hemihydrate calcium powder
End.
Preferably：In step (3), by mineralized collagen porous calcium phosphate composite material and α-sulfate hemihydrate calcium powder according to
5:5~3:7 mass ratio carries out the mixing.
Preferably：In step (3), in the mixture also include coagulant, the coagulant be selected from calcium sulphate dihydrate,
Any one of potassium sulfate, potassium chloride, quality account for 5~20wt% of mixture gross mass.
Preferably：It also include moulding dose in step (3), in the mixture, described moulding dose is selected from hydroxylmethyl cellulose
Any one of element, hydroxypropyl methyl cellulose, chitosan, quality account for 1~15wt% of mixture gross mass.
Preferably：In step (3), the sterilizing is carried out by the way of irradiation, reagent used is Co 60 bactericidal agent,
Dosage is 15~35kGy.
The artificial bone renovating material of Injectable self-curable is made using preparation method described above.
(3) advantageous effect
The above-mentioned technical proposal of the present invention has the following advantages that：
The present invention is prepared for biphasic calcium phosphate porous particle, and by porous calcium phosphate by special sintering process
Surface and gap prepare mineralized collagen, so that mineralized collagen is uniformly combined with porous calcium phosphate, collagen is uniformly in two-phase phosphoric acid
Calcium porous particle gap and surface mineralising, rather than simple blending so that material has good biocompatibility and certain branch
Support intensity；α-half-H 2 O calcium sulphate is introduced in system, and keeps its proportioning more scientific and reasonable so that material has the property of self-curing
Can, the requirement for injectable spontaneous coagulation in clinic is met, and material does not have temperature change in process of setting, for week
Tissue is enclosed not damage.In conclusion preparation method provided by the invention combines mineralized collagen, synthos, α-half water sulphur
The advantages of sour calcium, the shortcomings that overcoming each material, being made a kind of having medicine-carried, plasticity, can develop, injectable, can drop
The artificial bone renovating material of the features such as solution meets the needs of different clinics.
Artificial bone renovating material produced by the present invention is composite porous, is conducive to the growth of bone tissue and creeps replace
In generation, there is certain support strength, self-curing, can random-shaping, antibiotic and growth factor can be loaded, develop under X-ray, have
Conducive to inspection.
Artificial bone renovating material produced by the present invention is degradable, avoids secondary pain caused by taking out, degradation rate and new
Bone uptake rate-matched, can also be by adjusting the proportion adjustment degradation time of several ingredients.
Description of the drawings
Fig. 1 is the surface of the BMSCs cells artificial bone renovating material made from embodiment 1 arrived using scanning electron microscopic observation
Stick behavior；
Fig. 2 is the cytotoxicity experiment result of artificial bone renovating material made from embodiment 1；
Fig. 3 is the zoopery histotomy result of artificial bone renovating material made from embodiment 1.
Specific implementation mode
To make the object, technical solutions and advantages of the present invention clearer, below in conjunction with the embodiment of the present invention, to this hair
Bright technical solution is clearly and completely described.Obviously, described embodiment is a part of the embodiment of the present invention, and
The embodiment being not all of.Based on the embodiments of the present invention, those of ordinary skill in the art are not making creative work
Under the premise of the every other embodiment that is obtained, shall fall within the protection scope of the present invention.
The preparation method of the artificial bone renovating material of Injectable self-curable, the preparation method include the following steps：
(1) preparation of biphasic calcium phosphate porous particle：It prepares component and includes the first calcium salt, polyvinyl alcohol and PMMA microsphere,
Mass ratio is (0.1~0.5):3:2, first calcium salt is by hydroxyapatite and beta-calcium phosphate according to 5:1~1:3 mass ratio
Composition；
Preparation method includes：
(a) compound concentration is the poly-vinyl alcohol solution of 0.2~0.5g/mL；
(b) two-phase phosphate suspension is prepared；Hydroxyapatite and beta-calcium phosphate are added in PBS solution, formed outstanding
Turbid；
(c) poly-vinyl alcohol solution is added in the two-phase phosphate suspension, after stirring 0.5~1 hour, then is added
Enter PMMA microsphere, after stirring 0.5~1 hour, obtains sintering base fluid；
(d) the sintering base fluid is placed in agglomerating plant and is sintered, obtain agglomerated material；
The sintering includes such as the next stage：
First stage：Heating rate be 5~10 DEG C/min, target temperature be 400~800 DEG C, constant temperature time be 300~
350min；
Second stage：Heating rate be 5~10 DEG C/min, target temperature be 1000~1200 DEG C, constant temperature time be 180~
200min；
Phase III：Agglomerating plant is stopped heating, cooled to room temperature；
(e) agglomerated material is crushed；
(f) it sieves.
The present invention selects the calcium phosphate compound prescription of two-phase, preferably hydroxyapatite and β-TCP (i.e. beta-calcium phosphate) compound
Two-phase.In the biphasic calcium phosphate material of selection, the second calcium salt can also be added, the calcium salt is selected from type alpha tricalcium phosphate, two water
Any one or more calcium salts of calcium monohydrogen phosphate, calcium monohydrogen phosphate, tetracalcium phosphate, dosage account for the 1~10% of calcium salt gross mass.
The present invention is used as pore creating material using PMMA microsphere (poly (methyl methacrylate) micro-sphere).In some embodiments, institute
PMMA microsphere uses grain size for any one of 50~800 microns or two kinds, it is further preferred that, using grain size 50
~200 microns of poly (methyl methacrylate) micro-sphere and the poly (methyl methacrylate) micro-sphere of 400~600 microns of grain size are according to 2:
8~8:The mixture of 2 mass ratioes composition.
(2) preparation of mineralized collagen porous calcium phosphate composite material：Biphasic calcium phosphate porous particle is added to a concentration of 1
The collagen acid solution of~5mg/mL (when preparing the collagen acid solution, solvent can select any one of hydrochloric acid, nitric acid, acetic acid)
In, it is stirred 2~3 hours, is configured to the suspension of a concentration of 10~30wt%；
Continue stirred suspension, (in order to obtain preferable reaction effect, rate of addition is unsuitable too fast, is slowly added dropwise for dropwise addition
It is advisable) solution of calcium ions, the addition of calcium ion is that every gram of collagen corresponds to 0.01~0.15mol of calcium ion is added；It is added dropwise
The solution of (in order to obtain preferable reaction effect, rate of addition is unsuitable too fast, and being slowly added dropwise is advisable) phosphorus-containing acid ion, phosphoric acid
The molar ratio of radical ion and calcium ion is Ca/P=0.8~1.8；Lasting stirring, be added dropwise (in order to obtain preferable reaction effect,
Rate of addition is unsuitable too fast, and being slowly added dropwise is advisable) NaOH solution is to mixed system pH to 7~8, when pH reaches 5~6, mixing
System starts to precipitate, and when pH reaches 7, white suspension occurs in mixed system；Gained mixed system is stood 24~96
Hour, isolate precipitate and wash away foreign ion, be then freeze-dried, after grinding obtain mineralized collagen content be 2~
The mineralized collagen porous calcium phosphate composite material of 25wt%.
Mineralized collagen carries out precipitation arrangement in the surface and gap of biphasic calcium phosphate porous particle, can be more uniform
Distribution makes artificial bone renovating material have better bioactivity.
(3) mixture：By mineralized collagen porous calcium phosphate composite material and α-sulfate hemihydrate calcium powder according to 7:3~2:8
Mass ratio mixes, preferably according to 5:5~3:Injectable self-curable people is made through dry and sterilizing in 7 mass ratio mixing, mixture
Work bone renovating material.α-sulfate hemihydrate calcium powder can be prepared as follows：By calcium sulphate dihydrate, sodium citrate,
Aluminum sulfate and water are according to 1:0.0025:0.0025:5.67 mass ratio adds in reaction vessel, then seals and open stirring,
In 120 DEG C of conditioned response 6 hours；Reaction solution is filtered while hot after completion of the reaction, filter cake 3 is rinsed with deionization boiling water after suction filtration
~5 times, filter cake is then put into drying box 100 DEG C of dryings 12~24 hours, half-H 2 O calcium sulphate is made；Half-H 2 O calcium sulphate is ground
It clays into power, then is sieved with 100 mesh sieve, the powder of sieving is α-sulfate hemihydrate calcium powder.
In some embodiments, the mode that irradiation may be used carries out the sterilizing, and reagent used is Co 60 bactericidal agent,
Dosage is 15~35kGy.
In addition, also including coagulant in mixture, obtained includes the artificial bone renovating material of coagulant.Rush used is solidifying
Agent can be selected from any one of calcium sulphate dihydrate, potassium sulfate, potassium chloride, and dosage, which can control within the scope of 5~20wt%, (to be referred to
The quality of coagulant accounts for the 5~20% of mixture gross mass).The setting time of this artificial bone renovating material obtained can be 5
It is adjusted within~60 minutes, meets the use of different clinical operations.
In addition, also including moulding dose in mixture, obtained includes moulding dose of artificial bone renovating material.Used is moulding
Agent can be used for adjusting moulding, additionally it is possible to improve anti-collapsibility, preferably be selected from hydroxymethyl cellulose, hydroxypropyl methyl cellulose, shell
Any one of glycan, dosage control (refer to moulding dose of quality and account for the 1~15% of mixture gross mass) in 1~15wt%.
It is had the property that using artificial bone renovating material made from the above method：
(a) mineralized collagen is evenly distributed on surface and the hole of biphasic calcium phosphate porous particle, makes mineralized collagen equably
It is combined with porous calcium phosphate, to make artificial bone renovating material that there is better biocompatibility.
(b) artificial bone renovating material has porous structure, is not only advantageous to growth and the creeping substitution of bone tissue, also has
Certain support strength.
(c) artificial bone renovating material is also used as the carrier of growth factor and all kinds of antibiotic, carries out anti-inflammatory therapy.
(d) artificial bone renovating material develops under X-ray, is conducive in art and clinical follow.
(e) artificial bone renovating material is degradable, avoids secondary pain caused by taking out, and degradation rate can be with new bone
Growth rate matches.
(f) artificial bone renovating material can injectable in situ, and there is excellent self-curing performance.
It is the embodiment that the present invention enumerates below.
Embodiment 1
S1, hydro-thermal method prepare α-sulfate hemihydrate calcium powder
By CaSO4·2H2O is added in reaction kettle, takes account for CaSO respectively4·2H2The sodium citrate and sulphur of O mass 0.25%
Sour aluminium is added in reaction kettle, adds CaSO4·2H2The deionized water that 5.67 times of O mass, closed reactor, stirring, temperature are
It 120 DEG C, reacts 6 hours；Reaction solution is filtered while hot after completion of the reaction, rinses filter cake 5 times with deionization boiling water after suction filtration, entirely
Filtrate and irrigating fluid temperature are at 90 DEG C or more in the process；The filter cake drained is put into drying box 100 DEG C of dryings 12 hours, is made
α-half-H 2 O calcium sulphate；With mortar grinder, α-sulfate hemihydrate calcium powder of uniform particle diameter is made in the sieving of 100 mesh sieve.
S2, biphasic calcium phosphate porous particle is prepared
It includes the first calcium salt, polyvinyl alcohol and PMMA microsphere (PMMA microsphere and grain by grain size for 100 microns to prepare component
The PMMA microsphere that diameter is 500 microns is according to 1:The mixture of 1 mass ratio composition), mass ratio 0.4:3:2, first calcium
Salt is by hydroxyapatite and beta-calcium phosphate according to 1:3 mass ratio composition；
Preparation method includes：
(a) compound concentration is the poly-vinyl alcohol solution of 0.2g/mL；
(b) two-phase phosphate suspension is prepared；Hydroxyapatite and beta-calcium phosphate are added in PBS solution, formed outstanding
Turbid；
(c) poly-vinyl alcohol solution is added in the two-phase phosphate suspension, after stirring 0.8 hour, is added
PMMA microsphere after stirring 0.8 hour, obtains sintering base fluid；
(d) the sintering base fluid is placed in agglomerating plant and is sintered, obtain agglomerated material；
The sintering includes such as the next stage：
First stage：Heating rate is 10 DEG C/min, and target temperature is 800 DEG C, constant temperature time 300min；
Second stage：Heating rate is 10 DEG C/min, and target temperature is 1200 DEG C, constant temperature time 180min；
Phase III：Agglomerating plant is stopped heating, cooled to room temperature；
(e) agglomerated material is crushed；
(f) it sieves.
S3, mineralized collagen porous calcium phosphate composite material is prepared
Collagen is dissolved in hydrochloric acid, is configured to collagen acid solution, wherein collagen concentration is 1mg/mL；Biphasic calcium phosphate is porous
Particle is added thereto, and is stirred 2 hours, and suspension is formed, and suspension concentration is that (concentration representative is suspension to 10wt%
The quality of middle biphasic calcium phosphate porous particle accounts for the percentage of suspension quality)；
Above-mentioned suspension liquor is persistently stirred, the solution of calcium ions is slowly added dropwise, the addition of calcium ion is every gram of glue
Original is corresponding to be added calcium ion 0.01mol；The solution of phosphorus-containing acid ion, the molar ratio of phosphate anion and calcium ion is slowly added dropwise
For Ca/P=1.5；
Lasting stirring is slowly added dropwise NaOH solution and reaches 7~8 to mixed system pH, when the pH of system reaches 5~6, mixes
Zoarium system starts to precipitate, and when pH reaches 7, white suspension occurs in mixed system；
Gained mixed system is stood 24 hours, isolates and precipitates and wash away foreign ion, be then freeze-dried, ground
Mineralized collagen porous calcium phosphate composite material is obtained after mill.
Above-mentioned mineralized collagen carries out precipitation arrangement in the surface and gap of porous calcium phosphate, can more uniformly divide
Cloth, it is 4% so that integral material is had good bioactivity, mineralized collagen content.
S4, mixture
By mineralized collagen porous calcium phosphate composite material and α-sulfate hemihydrate calcium powder according to 5:5 mass ratio mixing, is mixed
It is that Injectable self-curable bone is repaiied afterwards that object, which is closed, through dry and irradiation sterilization (agents useful for same is Co 60 bactericidal agent, dosage 15kGy)
Multiple material, setting time are 30 minutes, and degradation time is a year and a half.
Stick behavior in material surface early stage by scanning electron microscopic observation BMSCs cells (i.e. mesenchymal stem cell),
Scanning electron microscope is by handling material and cell composite surface, the entire wheel of energy display material surface topography and adherent cell
Exterior feature has three-dimensional sense, while can meticulously observe the surface textures such as the stretching, extension of its pseudopodium, the secretion of matrix granule, can be objective
Evaluate influence of the surface modifying material to osteoblast metamorphosis in ground.As shown in Figure 1, bone renovating material tool produced by the present invention
There is good biocompatibility, sticking for cell can be promoted.
Fig. 2 shows the cytotoxicity experiment result of bone renovating material.As shown in Figure 2, it is co-cultured with bone renovating material
Cellular morphology is normal, adherent good, and acellular dissolving and apoptosis generate, and can determine that as 0 grade of cell-cytotoxic reaction.
Fig. 3 is 12 weeks after operation zoopery histotomy result.From figure 3, it can be seen that material has good Bone Defect Repari
Ability can complete the reparation of bone defect, it is seen that there is newborn bone trabecula in defective region, realizes that the proper alignment of bone trabecula, implant bed have
A large amount of area of new bone are grown into finger-like in bone graft, and cell component is abundant, it is seen that not degradable material is the maturation of bone tissue
More permanent support is provided.
Embodiment 2
It is substantially the same that the preparation method is the same as that of Example 1, the difference is that：
In S2：
It is 100 microns of PMMA microsphere as pore creating material to use grain size.
In S3：
A concentration of 5mg/mL of collagen acid solution, suspension concentration 20wt%；
Every gram of collagen, which corresponds to, is added calcium ion 0.05mol, and the molar ratio of phosphate anion and calcium ion is Ca/P=1.8；
It is 10% to obtain the mineralized collagen content in mineralized collagen porous calcium phosphate composite material.
In S4：
By mineralized collagen porous calcium phosphate composite material and α-sulfate hemihydrate calcium powder according to 3:7 mass ratio mixing, coagulates
Gu the time is 20 minutes, degradation time is 1 year.
Embodiment 3
It is substantially the same that the preparation method is the same as that of Example 1, the difference is that：
In S2：
It is 800 microns of PMMA microsphere as pore creating material to use grain size.
In S3：
A concentration of 3mg/mL of collagen acid solution, suspension concentration 30wt%；
Every gram of collagen, which corresponds to, is added calcium ion 0.15mol；
It is 15% to obtain the mineralized collagen content in mineralized collagen porous calcium phosphate composite material.
In S4：
By mineralized collagen porous calcium phosphate composite material and α-sulfate hemihydrate calcium powder according to 7:3 mass ratio mixing, coagulates
Gu the time is 60 minutes, degradation time is 2 years.
Embodiment 4
It is substantially the same that the preparation method is the same as that of Example 1, the difference is that：
In S2：
Use the PMMA microsphere (mass ratio 1 that grain size is 400 microns for 50 microns of PMMA microsphere+grain size:1) it is used as and makes
Hole agent.
In S3：
A concentration of 5mg/mL of collagen acid solution, suspension concentration 30wt%；
Every gram of collagen, which corresponds to, is added calcium ion 0.1mol；
It is 3% to obtain the mineralized collagen content in mineralized collagen porous calcium phosphate composite material.
In S4：
By mineralized collagen porous calcium phosphate composite material and α-sulfate hemihydrate calcium powder according to 2:8 mass ratio mixing solidification
15 minutes time, degradation time nine months.
Embodiment 5
Preparation method is substantially the same with embodiment 4, the difference is that：
In S4, it is also added into calcium sulphate dihydrate, additive amount is the 10wt% of mixture gross mass, composite material obtained
In include calcium sulphate dihydrate, add coagulant, setting time can shorten to 10 minutes.
Embodiment 6
Preparation method is substantially the same with embodiment 5, the difference is that：
Chitosan is also added into S4, additive amount is the 10wt% of mixture gross mass, is wrapped in composite material obtained
Chitosan-containing.
Comparative example 1
It is substantially the same that the preparation method is the same as that of Example 1, the difference is that：In S2, only with hydroxyapatite conduct
Component is prepared, sintering feed is compounded into PMMA microsphere.
Comparative example 2
It is substantially the same that the preparation method is the same as that of Example 1, the difference is that：In S2, the grain size of pore creating material used is
10 microns.
Comparative example 3
It is substantially the same that the preparation method is the same as that of Example 1, the difference is that：In S2, the grain size of pore creating material used is
1000 microns.
Comparative example 4
It is substantially the same that the preparation method is the same as that of Example 1, the difference is that：In S2, sintering carries out as follows：
Sintering feed is directly warming up to 1000 DEG C, is sintered at such a temperature, sintering time is the same as embodiment 1.
Comparative example 5
It is substantially the same that the preparation method is the same as that of Example 1, the difference is that：S3 is carried out as follows：
Collagen is dissolved in hydrochloric acid, is configured to collagen acid solution, the wherein a concentration of 1mg/mL of collagen acid solution；
Above-mentioned suspension liquor is persistently stirred, the solution of calcium ions is slowly added dropwise, the addition of calcium ion is every gram of glue
Original is corresponding to be added calcium ion 0.01mol；The solution of phosphorus-containing acid ion, the molar ratio of phosphate anion and calcium ion is slowly added dropwise
For Ca/P=1.5；
Lasting stirring is slowly added dropwise NaOH solution and reaches 7~8 to mixed system pH, when the pH of system reaches 5~6, mixes
Zoarium system starts to precipitate, and when pH reaches 7, white suspension occurs in mixed system；
Gained mixed system is stood 24 hours, isolates and precipitates and wash away foreign ion, be then freeze-dried, ground
Mineralized collagen is obtained after mill；
By biphasic calcium phosphate porous particle and mineralized collagen according to 1:0.4 mass ratio mixes, and obtains the porous phosphorus of mineralized collagen
Sour calcium composite material.
Comparative example 6
It is substantially the same that the preparation method is the same as that of Example 1, the difference is that：In S4, by mineralized collagen porous calcium phosphate
Composite material and α-sulfate hemihydrate calcium powder are according to 1：0.1 mass ratio mixing.
The performance of bone renovating material made from each comparative example is detected, test result is as shown in table 1.
Table 1
It can be seen that from the testing result of comparative example 1, comparative example 2, comparative example 3, comparative example 4 in sintered porous calcium phosphate
When particle, the mixture of component, the grain size of pore creating material and sintering condition all influence the performance of bone renovating material.Comparative example 5 is independent
Mineralized collagen is prepared, then biphasic calcium phosphate porous particle obtained in its abovementioned steps is mixed, bone renovating material obtained
Biocompatibility is obviously not as good as the present invention.Mineralized collagen porous calcium phosphate composite wood is can be seen that from the testing result of comparative example 6
The mixed ratio of material and α-sulfate hemihydrate calcium powder also has large effect to the performance of bone renovating material.
To sum up, the present invention is prepared for biphasic calcium phosphate porous particle, and by porous phosphorus by special sintering process
Sour calcium surface and gap prepare mineralized collagen, so that mineralized collagen is uniformly combined with porous calcium phosphate so that material has good
Biocompatibility and certain support strength；α-half-H 2 O calcium sulphate is introduced in system, and keeps its proportioning more scientific and reasonable, is made
Obtaining material has the performance of self-curing, meets the requirement for injectable spontaneous coagulation in clinic, and material is in process of setting
In there is no temperature change, surrounding tissue is not damaged.In conclusion preparation method provided by the invention combines mineralising glue
The advantages of original, synthos, α-half-H 2 O calcium sulphate, the shortcomings that overcoming each material, being made a kind of having medicine-carried, plastic
Property, can develop, injectable, it is degradable the features such as bone renovating material, meet it is different clinic the needs of.
Finally it should be noted that：The above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations；Although
Present invention has been described in detail with reference to the aforementioned embodiments, it will be understood by those of ordinary skill in the art that：It still may be used
With technical scheme described in the above embodiments is modified or equivalent replacement of some of the technical features；
And these modifications or replacements, various embodiments of the present invention technical solution that it does not separate the essence of the corresponding technical solution spirit and
Range.
Claims (10)
1. the preparation method of the artificial bone renovating material of Injectable self-curable, it is characterised in that：The preparation method includes following step
Suddenly：
(1) preparation of biphasic calcium phosphate porous particle：It includes the first calcium salt, polyvinyl alcohol and PMMA microsphere, quality to prepare component
Than for (0.1~0.5):3:2, first calcium salt is by hydroxyapatite and beta-calcium phosphate according to 5:1~1:3 mass ratio group
At；
Preparation method includes：
(a) compound concentration is the poly-vinyl alcohol solution of 0.2~0.5g/mL；
(b) two-phase phosphate suspension is prepared；Hydroxyapatite and beta-calcium phosphate are added in PBS solution, suspension is formed；
(c) poly-vinyl alcohol solution is added in the two-phase phosphate suspension, after stirring 0.5~1 hour, is added
PMMA microsphere after stirring 0.5~1 hour, obtains sintering base fluid；
(d) the sintering base fluid is placed in agglomerating plant and is sintered, obtain agglomerated material；
The sintering includes such as the next stage：
First stage：Heating rate be 5~10 DEG C/min, target temperature be 400~800 DEG C, constant temperature time be 300~
350min；
Second stage：Heating rate be 5~10 DEG C/min, target temperature be 1000~1200 DEG C, constant temperature time be 180~
200min；
Phase III：Agglomerating plant is stopped heating, cooled to room temperature；
(e) agglomerated material is crushed；
(f) it sieves；
(2) preparation of mineralized collagen porous calcium phosphate composite material：Biphasic calcium phosphate porous particle is added to a concentration of 1~
In the collagen acid solution of 5mg/mL, it is stirred 2~3 hours, is configured to the suspension of a concentration of 10~30wt%；
Continue stirred suspension, the solution of calcium ions is added dropwise, the addition of calcium ion is that every gram of collagen corresponds to addition calcium ion
0.01~0.15mol；Be added dropwise the solution of phosphorus-containing acid ion, the molar ratio of phosphate anion and calcium ion be Ca/P=0.8~
1.8；NaOH solution is added dropwise to mixed system pH to 7~8 in lasting stirring, and when pH reaches 5~6, mixed system starts to sink
It forms sediment, when pH reaches 7, white suspension occurs in mixed system；Gained mixed system is stood 24~96 hours, isolates precipitation
And foreign ion is washed away, it is then freeze-dried, it is more that the mineralized collagen that mineralized collagen content is 2~25wt% is obtained after grinding
Hole calcium phosphate composite material；
(3) mixture：By mineralized collagen porous calcium phosphate composite material and α-sulfate hemihydrate calcium powder according to 7:3~2:8 quality
Than mixing, the artificial bone renovating material of Injectable self-curable is made through dry and sterilizing in mixture.
2. preparation method according to claim 1, it is characterised in that：In step (1), the PMMA microsphere uses grain size
It is any one of 50~800 microns or two kinds；The preferably PMMA microsphere and grain size 400~600 of 50~200 microns of grain size
The PMMA microsphere of micron is according to 2:8~8:The mixture of 2 mass ratioes composition.
3. preparation method according to claim 1, it is characterised in that：In step (1), prepares and be also included in step in component
Suddenly the second calcium salt being added in (b), second calcium salt are selected from type alpha tricalcium phosphate, dicalcium phosphate dihydrate, calcium monohydrogen phosphate, phosphoric acid four
Calcium any one or more of, dosage account for the 1~10% of calcium salt gross mass.
4. preparation method according to claim 1, it is characterised in that：In step (2), the collagen acid solution institute is prepared
Solvent is selected from any one of hydrochloric acid, citric acid, acetic acid.
5. preparation method according to claim 1, it is characterised in that：In step (3), the α-sulfate hemihydrate calcium powder
It is prepared as follows：
By calcium sulphate dihydrate, sodium citrate, aluminum sulfate and water according to 1:0.0025:0.0025:5.67 mass ratio adds to reaction
In container, stirring is then sealed and opens, in 120 DEG C of conditioned response 6 hours；Reaction solution is filtered while hot after completion of the reaction,
Filter cake 3~5 times is rinsed with deionization boiling water after suction filtration, filter cake is then put into drying box 100 DEG C of drying 12~24 hours, is made
Obtain half-H 2 O calcium sulphate；
It is sieved by half-H 2 O calcium sulphate grind into powder, then with 100 mesh sieve, the powder of sieving is α-sulfate hemihydrate calcium powder.
6. preparation method according to claim 1, it is characterised in that：In step (3), by mineralized collagen porous calcium phosphate
Composite material and α-sulfate hemihydrate calcium powder are according to 5:5~3:7 mass ratio carries out the mixing.
7. preparation method according to claim 1, it is characterised in that：Also include to promote in step (3), in the mixture
Solidifying agent, the coagulant are selected from any one of calcium sulphate dihydrate, potassium sulfate, potassium chloride, quality account for mixture gross mass 5~
20wt%.
8. preparation method according to claim 1, it is characterised in that：Also include modeling in step (3), in the mixture
Shape agent, described moulding dose is selected from any one of hydroxymethyl cellulose, hydroxypropyl methyl cellulose, chitosan, and quality accounts for mixing
1~15wt% of object gross mass.
9. preparation method according to claim 1, it is characterised in that：In step (3), institute is carried out by the way of irradiation
Sterilizing is stated, reagent used is Co 60 bactericidal agent, and dosage is 15~35kGy.
10. the artificial bone renovating material of Injectable self-curable, it is characterised in that：Using any one of claim 1 to the 9 preparation side
Method is made.
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