CN108478879A - A kind of porous calcium phosphate/natural polymer compound rest and the preparation method and application thereof - Google Patents
A kind of porous calcium phosphate/natural polymer compound rest and the preparation method and application thereof Download PDFInfo
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- CN108478879A CN108478879A CN201810276029.0A CN201810276029A CN108478879A CN 108478879 A CN108478879 A CN 108478879A CN 201810276029 A CN201810276029 A CN 201810276029A CN 108478879 A CN108478879 A CN 108478879A
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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
- 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
-
- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/08—Methods for forming porous structures using a negative form which is filled and then removed by pyrolysis or dissolution
-
- 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 invention discloses a kind of porous calcium phosphate/natural polymer compound rests and the preparation method and application thereof.This method produces the full communicating polymeric stent of hole as sacrifice model first with 3D printing, it is placed in mold, then natural polymer microballoon and calcium phosphate bone cement are uniformly mixed and made into slurry, it is poured into model, slurry is set to fill up model hole, high score submodel is removed with solvent again, obtains connected porous calcium phosphate/natural polymer compound rest.Present invention incorporates the low temperature self-curing of bone cement, excellent mechanical performances and natural polymer high bioactivity, degradable features, prepare the compound rest of three-dimensional communication macroporous structure.The right polymer microsphere fast degradation day after tomorrow, is formed in situ hierarchical porous structure in stenter to implant body.It need not make bioactivity and good mechanical properties through high-temperature process in the preparation process of the present invention, structure and degradation rate are controllable, are conducive to growing into for bone tissue and blood vessel, improve Bone Defect Repari effect.
Description
Technical field
The invention belongs to bone injuries to repair field of medical materials, and in particular to a kind of porous calcium phosphate/natural polymer is multiple
Close holder and the preparation method and application thereof.
Background technology
Bone carries very important effect, but be easy to due to various reasons as the maximum histoorgan of human body
Cause bone defect.Modern society, the bone defect patient caused by wound, aging, inflammation, tumour and congenital malformation disregard
It is counted, but clinically for the reparation of bone defect especially large segmental bone defect still without effective means.Although bone has certainly
Heal function, but large segmental bone defect can not be repaired only by body completely, in this case with regard to needing to carry out to repairing
Foreign intervention auxiliary treatment.The foreign intervention clinically used at present includes autologous bone transplanting, bone xenograft and implantation people
Bone renovating material etc. is made, but since there are various problems and risk for bone collection application, therefore develops bone tissue engineer and existed using holder
Maintaining to improve its function osteogenic tissue that lays equal stress in vivo becomes the target pursued jointly of the numerous scientists in the whole world.
Timbering material for Bone Defect Repari should meet claimed below：(1) good biocompatibility and osteoconductive；(2)
With suitable aperture, porosity and connectivity；(3) there is the mechanical property to match with bone defect position；(4) degradation speed
With bone remoulding speeds match.In numerous bone tissue engineering stent materials, calcium phosphate bone cement (Calcium phosphate
Cement, CPC) have that similar to the inorganic constituents of bone tissue, osteoconductive is good, can low temperature self-curing, degradable absorbable, easily
It is moulding, can be used for carry medicine the advantages that, these advantages can largely meet the requirement of clinical Bone Defect Repari, have other bones to repair
The unexistent advantage of multiple material.But there is the shortcomings that relatively slow degradation, shortage three-dimensional communication macropore in CPC firming bodys, and three-dimensional is even
Vascularization and bone tissue generation of the logical macropore during Bone Defect Repari grow into and play very crucial effect.Hole is thought in many researchs
Diameter reaches the high bone renovating material of 50%-90%, hole connectivity and is more advantageous to Bone Defect Repari more than 300 μm, porosity.
Realize that the method for three-dimensional communication macroporous structure mainly has particulate leaching method, lotion cold in calcium phosphate bone cement material
Freeze seasoning, fiber solid intertexture method, 3D printing method, foaming, ira situ degradation pore-forming etc..(the Dennis such as Dennis P
P.Link,Juliette van den Dolder,et al.Mechanical evaluation of implanted
calcium phosphate cement incorporated with PLGA microparticles.Biomaterials
2006,27:4941-4947) in CPC compound 20wt.% PLGA microballoons, PLGA fails when results of animal shows 2 weeks
Degradation, freshman bone tissue are replaced, PLGA after 8 weeks only in material surface as it can be seen that part PLGA starts to degrade at 4 weeks by bone tissue
Degradation is complete, and area of new bone is whole all visible in material.(Anja Lode, the Katrin Meissner, et such as Anja Lode
al.Fabrication of porous scaffolds by three-dimensional plotting of a pasty
calcium phosphate bone cement under mild conditions.Journal of tissue
Engineering and Regenerative Medicine 2014；8:682-693) by bone cement powder, glycerine, tween-
80 and phosphoric acid cetyl ester be uniformly mixed as slurry, obtain CPC holders, Ci Zhongfang using maintenance after 3D plotting printings
Holder prepared by method has good mechanical property and biocompatibility, but there is also deficiency, bottom and lateral macropores simultaneously
It is easy to be blocked.Traditional pore forming method has that aperture, hole connected ratio, pore structure controllable degree be low, bracket geometry is not easy
The shortcomings of control.Although 3D printing can accurately control the geometric shape and internal structure of holder, personalized Bone Defect Repari is prepared
Material, but 3D printing is to build holder by method that material layers are superimposed, directly carrying out printing using inorganic slurry can be by
Having little time solidification in fiber causes fiber by gravity deformation, causes holder sidewise hole and bottom hole plug, repetitive rate low.And then it is
Overcome the defect of above-mentioned technology, the patent of Patent No. 201610559602.X discloses a kind of using answering macromolecule network
Close CPC prepare can ira situ degradation form the composite material of three-dimensional connected porous structure, such method can be controlled and is formed in situ very well
Three-dimensional macropore structure and diameter, and can ensure that the connectivity between macropore.Nevertheless, there is also lack for such method
It falls into, three-dimensional macropore is the formation of macromolecule network ira situ degradation, therefore is unfavorable for early stage cell and letter before macromolecule network degradation
The recruitment of number molecule is grown into material internal and freshman bone tissue and blood vessel；Macromolecule network degradation pore-forming also has drawback,
As PLGA and PLA can because degrade it is too fast caused by local environment peracid cause acid inflammation, PCL degraded slow influence freshman bone tissue
And blood vessel is grown into, and is unfavorable for Bone Defect Repari.
Bone tissue engineering stent material can also be natural polymer, such as gelatin, collagen, chitosan, agarose.
Natural polymer have ingredient close to extracellular matrix components, bioactivity height, good biocompatibility, good degradability and carefully
The advantages that born of the same parents' compatibility is excellent, and ingredient of degrading can provide raw material needed for cell metabolism, be cell and group after ira situ degradation
It knits and grows into vacating space.But mechanical strength difference and degradation rate is too fast that it is made to be restricted in practical applications.
The good biological activity of natural polymer, readily degradable are combined with low temperature self-curing, the excellent mechanical performances of CPC
Get up, the 3D printing macromolecule for being filled into hole and tactical rule is sacrificed in model, and high score submodel is removed after solidification, is prepared
A kind of porous calcium phosphate/natural polymer compound rest.By the comprehensive regulation to technological parameter, can prepare with good power
Learn the compound rest of performance and the aperture of biology performance and suitable Bone Defect Repari, porosity and degradation rate.
Invention content
In order to overcome the shortcomings that preparing porous calcium phosphate timbering material at present, the primary purpose of the present invention is that providing a kind of
Porous calcium phosphate/natural polymer compound rest.The compound rest of the present invention has controllable regular three-dimensional communication macropore, can show
It writes and increases surface area, the recruitment of cell and signaling molecule, and no cytotoxicity can be promoted；Natural polymer therein is being implanted into
Early stage can promote cell adhesion and proliferation in vivo, and hierarchical porous structure is formed after fast degradation, improve porosity, be conducive to area of new bone
Tissue and blood vessel are grown into, and improve the degradability of material, improve Bone Defect Repari effect.
Another object of the present invention is to provide the preparation methods of above-mentioned porous calcium phosphate/natural polymer compound rest.
The macromolecule that the three-dimensional communication with certain pore structure is obtained first with 3D printing sacrifices model, then by CPC and naturally
Slurry is poured into wherein made of polymer microsphere mixing reconciles, and high score submodule is removed using organic solvent after molding to be solidified
Porous calcium phosphate/natural polymer compound rest is finally prepared in type.Not only preparation process is simple and efficient for this kind of method, has
Effect overcomes direct 3D printing calcium phosphate because fiber is layering the unfavorable problem that printing generates, and with controllable shape and interior
Portion's porous structure.Model structure parameter is sacrificed by regulation and control, the three-dimensional communication macroporous structure of compound rest can be carried out personalized
Customization；By regulating and controlling the crosslinking time and content of natural polymer microballoon, change microballoon degradation time and in-situ pore-formed hole
Rate to make holder have suitable mechanical property and degradation rate, and improves the biology performance of timbering material, effectively improves
The skeletonization of timbering material and at vessel patency.
It is still another object of the present invention to provide above-mentioned porous calcium phosphate/natural polymer compound rests in bone defect healing
In application.
The purpose of the invention is achieved by the following technical solution.
A kind of preparation method of porous calcium phosphate/natural polymer compound rest, includes the following steps：
(1) the full communicating macromolecule of prefabricated hole sacrifices model：It is provided using the printing of 3D printer high molecular material
There are given configuration size and the full communicating macromolecule of internal structure, hole to sacrifice model；
(2) calcium phosphate bone cement and natural polymer microballoon mixture slurry are prepared：By self-curable calcium phosphate bone cement powder
It is uniformly mixed with natural polymer microballoon, solidify liquid is then added and reconciles uniformly, obtains calcium phosphate bone cement and natural polymer
Microballoon mixture slurry；
(3) mixture slurry and maintenance is perfused：Macromolecule prepared by step (1) is sacrificed model to be put into and appearance and size phase
In the matching die matched, then calcium phosphate bone cement prepared by step (2) is fed into natural polymer microballoon mixture slurry
Macromolecule is sacrificed in model, and slurry is made to fill up the hole of model, utilizes coagulation forming of self-curing characteristic of bone cement, demoulding
It conserves afterwards, is dry, obtaining macromolecule and sacrifice model/calcium phosphate bone cement/natural polymer microballoon composite curing body；
(4) removal macromolecule sacrifices model：Macromolecule sacrifice model/calcium phosphate bone cement that step (3) is obtained/natural
Polymer microsphere composite curing body, which is placed in organic solvent, to be impregnated, and is removed macromolecule and is sacrificed model, is then dried, is washed, does again
It is dry, obtain porous calcium phosphate/natural polymer compound rest of three-dimensional communication.
Preferably, step (1) high molecular material selects polycaprolactone (PCL), makrolon (PC), polyurethane
(TPU), one or more blends in polyhydroxyalkanoate (PHA), polylactic acid (PLA).
Preferably, the structural parameters of step (1) the macromolecule sacrifice model are：Fibre diameter is 200-600 μm, fiber
Spacing is 1-2mm, is 100-1700 μm by pore size control by adjusting fibre diameter and spacing.
Preferably, the mass ratio of step (2) the calcium phosphate bone cement powder and natural polymer microballoon is (90-99)：
(1-10)；The liquid-solid ratio of the calcium phosphate bone cement and natural polymer microballoon mixture slurry is 0.4-0.7mL/g.
Preferably, step (2) described calcium phosphate bone cement is tetracalcium phosphate+dicalcium phosphate dihydrate, unformed calcium phosphate+two
Water calcium monohydrogen phosphate, tetracalcium phosphate+type alpha tricalcium phosphate+calcium monohydrogen phosphate, partially crystallized calcium phosphate+calcium monohydrogen phosphate+hydroxyapatite, phosphorus
Any one in sour hydrogen calcium+type alpha tricalcium phosphate+calcium carbonate and tetracalcium phosphate-calcium monohydrogen phosphate system bone cement.
Preferably, step (2) the natural polymer microballoon raw material is gelatin, chitosan, glucan, polyaminoacid and glue
It is one or more in original.
Preferably, step (2) the natural polymer microballoon is prepared using emulsion-crosslinking method, using Geniposide conduct
Cross-linking agent solution is crosslinked, crosslinking time 6-24h；The grain size of the natural polymer microballoon is 53-212 μm.
Preferably, step (3) maintenance, which is placed in the climatic chamber that temperature is 37 DEG C, relative humidity is 97%, supports
Protect 72~120h.
Preferably, step (3) described drying is dry 24~48h at 37~60 DEG C.
Preferably, step (4) described organic solvent is dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, N, N-
It is one or more in dimethylformamide and butanone.
Preferably, the time of step (4) described immersion is 3h, is changed the liquid once per hour.
Preferably, step (4) drying, washing, re-dry are specifically that first at 37~60 DEG C, vacuum drying for 24 hours, removes
Remaining organic solvent, then cleaned 3 times with deionized water, 24~48h is then dried at 37~60 DEG C.
A kind of porous calcium phosphate/natural polymer the compound rest obtained by above-described preparation method, the porous phosphorus
Sour calcium/natural polymer compound rest matrix is the calcium phosphate bone cement firming body with three-dimensional communication macroporous structure, bone cement
Compound degradable natural polymer microballoon in firming body, macro porosity led 25%-45%, aperture are 200-600 μm.
The porous calcium phosphate that the present invention is prepared by indirect 3D printing/natural polymer compound rest, by having three
Self-curable calcium phosphate (CPC) matrix and polymer microsphere three-dimensional of dimension connection macroporous structure are combined, and can give full play to branch
The good biological activity that the three-dimensional communication macropore that frame itself has has with natural polymer microballoon, the effect of readily degradable have
Effect promotes the infiltration of early stage cell, bone tissue and blood vessel to grow into, and improves the degradation rate and area of new bone replacement in implantation later stage
Effect can apply in bone defect healing.
Compared with prior art, the invention has the advantages that and advantageous effect：
1, porous calcium phosphate/natural polymer compound rest that the present invention is prepared using indirect 3D printing technique prepares work
Skill is simple and efficient, can be realized personalized according to the geometric shape and internal structure for needing to accurately control holder of different patients
Customization.
2, porous calcium phosphate/natural polymer compound rest prepared by the present invention has the macropore knot of complete three-dimensional communication
Structure, specific surface area is larger, is conducive to recruitment and absorption of the internal stent to stem cell and signaling molecule, promotes Bone Defect Repari early stage
Bone tissue and blood vessel are grown into.Compound natural polymer microballoon promotes sticking and being proliferated for cell in bone cement matrix, after
The macropore that dispersion can be formed after phase degradation improves porosity, further promotes the degradation of bone cement matrix, is conducive to accelerate skeletonization
And vascularization.
3, porous calcium phosphate/natural polymer compound rest prepared by the present invention, it is compound micro- in bone cement by changing
The content of ball and micro-sphere crosslinked time adjust microballoon degradation rate and porosity, can play control compound rest degradation rate
Effect.
4, the phase can form multi-stage porous knot to porous calcium phosphate/natural polymer compound rest prepared by the present invention after the implantation
Structure, the 53- formed after the 200-600 μm of three-dimensional communication macropore formed after being removed by sacrifice model, the degradation of natural polymer microballoon
The submicron/nanometer hole composition that 212 μm of dispersion macropore and CPC matrixes aquations itself are formed, is conducive to nutriment and new old generation
Transport and the gas exchanges for thanking to product promote sticking, be proliferated and breaking up for cell, contribute to formation and the length of bone tissue and blood vessel
Enter, improves Bone Defect Repari effect.
5, the preparation method of porous calcium phosphate provided by the invention/natural polymer compound rest is to utilize calcium phosphate bone
The low temperature self-curing characteristic of cement is used in combination solvent to remove macromolecule sacrifice model at normal temperatures and obtains three-dimensional communication macroporous structure,
Whole preparation process need not be through high-temperature process, and gained holder activity is high, a large amount of micro-nano holes and day existing for bone cement matrix
Right polymer microsphere can be used in the load of drug and albumen.
Description of the drawings
Fig. 1 is the porous structure schematic diagram that embodiment 1 prepares calcium phosphate/gelatin-compounded holder.
Fig. 2 a are the scanning electron microscope (SEM) photograph that PCL sacrifices model in embodiment 1.
Fig. 2 b are the microscope figure of gelatine microsphere in embodiment 1.
Fig. 3 a are the upper surface scanning electron microscope (SEM) photograph of porous calcium phosphate/gelatine microsphere compound rest in embodiment 1.
Fig. 3 b are the profile scanning electron microscope of porous calcium phosphate/gelatine microsphere compound rest in embodiment 1.
Fig. 4 a are mouse mesenchymal cell in embodiment 1 in porous calcium phosphate/gelatine microsphere compound rest culture 1 day
Activity figure.
Fig. 4 b are mouse mesenchymal cell in embodiment 1 in porous calcium phosphate/gelatine microsphere compound rest culture 3 days
Activity figure.
Fig. 4 c are mouse mesenchymal cell in embodiment 1 in porous calcium phosphate/gelatine microsphere compound rest culture 5 days
Cell adhesion figure.
Specific implementation mode
The specific implementation of the present invention is described further with reference to embodiment and attached drawing, but embodiments of the present invention
It is not limited to that.
Embodiment 1
Select PCL (Mn=45000) as cast material is sacrificed, it is " phosphorus that natural polymer, which selects gelatin, bone cement system,
Sour four calcium+calcium monohydrogen phosphate (molar ratio 1:1) ", implementation steps include：
(1) 3D-Bioplotter is usedTMThe prefabricated PCL cylinders of printer sacrifice model：PCL is put into high temperature barrel, is selected
With the syringe needle of 300 μm of internal diameters, setting heating temperature is 180 DEG C.Utilize AutoCAD Software for Design diameter 8mm, the cylinder of high 5mm
Body Model imports Bioplotter RP delamination softwares and carries out layered shaping to it, layer height is 240 μm, then will be layered
File imports Visual Machines softwares, and setting model internal fiber stack manner is 0 ° and 90 ° and replaces successively, between fiber
Away from for 1mm.Adjusting platform temperature is 4 DEG C after keeping the temperature 20min, and nitrogen extrusion pressure is 1.6bar, and fiber squeezes out print speed and is
Then 5mm/s is printed to obtain and is sacrificed model.
(2) emulsion-crosslinking method prepares gelatine microsphere：The preparation that document Biomaterials 96 (2016) 33-46 is introduced
Gelatine microsphere method is improved, and the 15wt.% aqueous gelatin solutions of 20mL are slowly injected into and are heated in 50 DEG C of water-baths
In 100mL atoleine+0.5mL Span-80 mixed solutions, stirring and emulsifying 20min, then ice bath cures 20min, then slowly adds
Enter 10mL Geniposides ethanol solution [Geniposide a concentration of 0.5% (g/ml)], crosslinking is each with ice-cold petroleum ether and ethyl alcohol afterwards for 24 hours
Cleaning 3 times is sieved after freeze-drying and takes 53-106 μm of gelatine microsphere spare.
(3) calcium phosphate bone cement and microballoon compounding and pouring, molding：Gelatine microsphere is uniformly mixed with bone cement powder, it is bright
Glue microspheres amount is 5wt.%, in the ratio of 0.7mL/g by Na2HPO4-NaH2PO4Solidify liquid (0.25M Na2HPO4Aqueous solution and
0.25M NaH2P O4Aqueous solution is with volume ratio 1:1 is formulated) it is mixed with composite granule, reconcile into mixture slurry.PCL is sacrificial
Domestic animal model is placed in the mold that appearance and size matches, and mixture slurry is filled into model with perfusion tool, and appropriate pressurization makes
Slurry adequately fills up mold, is demoulded after 30min, and sample is put into 37 DEG C, conserves 72h in the climatic chamber of 97% humidity, then
It is placed on drying in 37 DEG C of baking ovens and for 24 hours, obtains PCL/ calcium phosphate bone cements/gelatine microsphere complex.
(4) model is sacrificed in removal, obtains compound rest：PCL/ calcium phosphate bone cements/gelatine microsphere complex is placed in two
3h is impregnated in chloromethanes, replaces a solvent per hour, removes PCL.Then it is dried in vacuo at 40 DEG C for 24 hours, uses deionized water
Cleaning 3 times is placed in drying in 37 DEG C of baking ovens and for 24 hours, obtains porous calcium phosphate/gelatin-compounded holder (see Fig. 1).
PCL manufactured in the present embodiment sacrifices the complete three-dimensional communication of model hole gap, and fibre diameter is about 280 μm, and aperture is big
About 710 μm (see Fig. 2 a).Gelatine microsphere is rounded, and dispersibility is preferably (see Fig. 2 b).The porous calcium phosphate finally prepared/bright
The macroporous structure of glue microballoon compound rest remains intact, and gelatine microsphere is evenly distributed on rack surface and inside, gelatine microsphere drop
Dispersion hole is left after solution (see Fig. 3 a, Fig. 3 b).The connection macropore diameter of this compound rest is 282 ± 17 μm, connection macropore hole
Gap rate is 38.15 ± 2.00%, and compression strength is 2.45 ± 0.36MPa；After external degradation 28 days, gelatine microsphere Partial digestion.
Porous calcium phosphate/gelatin-compounded holder good biocompatibility is proved through In vitro cell experiment, non-toxic, system of Himdu logic cellula adhesiae compatibility
It is good, therefore grow that the surfaces cell quantity ratio CPC sticked are more on gelatine microsphere surface, microballoon degrade the hole to be formed be conducive to plus
Fast material degradation promotes skeletonization and vascularization (see Fig. 4 a, Fig. 4 b, Fig. 4 c).
Embodiment 2
Select PCL (Mn=45000) as cast material is sacrificed, it is " portion that natural polymer, which selects gelatin, bone cement system,
Divide crystallized calcium phosphate+calcium monohydrogen phosphate+hydroxyapatite (mass ratio 45:45:10) ", implementation steps include：
(1) 3D-Bioplotter is usedTMThe prefabricated PCL cylinders of printer sacrifice model：PCL is put into high temperature barrel, is selected
With the syringe needle of 300 μm of internal diameters, setting heating temperature is 180 DEG C.Utilize AutoCAD Software for Design diameter 8mm, the cylinder of high 5mm
Body Model imports Bioplotter RP delamination softwares and carries out layered shaping to it, layer height is 240 μm, then will be layered
File imports Visual Machines softwares, and setting model internal fiber stack manner is 0 ° and 90 ° and replaces successively, between fiber
Away from for 1mm.Platform temperature is adjusted after heat preservation 20min and is set as 4 DEG C, and nitrogen extrusion pressure is 1.6bar, and fiber squeezes out printing speed
Degree is 5mm/s, is then printed to obtain model.
(2) emulsion-crosslinking method prepares gelatine microsphere：The preparation that document Biomaterials 96 (2016) 33-46 is introduced
Gelatine microsphere method is improved, and the 15wt.% aqueous gelatin solutions of 20mL are slowly injected into and are heated in 50 DEG C of water-baths
In 100mL atoleine+0.5mL Span-80 mixed solutions, stirring and emulsifying 20min, then ice bath cures 20min, then slowly adds
Enter 10mL Geniposides ethanol solution [Geniposide a concentration of 0.5% (g/ml)], crosslinking is each with ice-cold petroleum ether and ethyl alcohol afterwards for 24 hours
Cleaning 3 times is sieved after freeze-drying and takes 53-106 μm of gelatine microsphere spare.
(3) calcium phosphate bone cement and microballoon compounding and pouring, molding：Gelatine microsphere is uniformly mixed with bone cement powder, it is bright
Glue microspheres amount is 2wt.%, mixes deionized water with composite granule in the ratio of 0.55mL/g, reconciles into mixture slurry.It will
PCL sacrifices model and is placed in the mold that appearance and size matches, and mixture slurry is filled into model with perfusion tool, appropriate to add
Pressure makes slurry adequately fill up mold, is demoulded after 30min, and sample is put into 37 DEG C, and 72h is conserved in the climatic chamber of 97% humidity,
Then it is placed on drying in 37 DEG C of baking ovens and for 24 hours, obtains PCL/ calcium phosphate bone cements/gelatine microsphere complex.
(4) model is sacrificed in removal, obtains compound rest：PCL/ calcium phosphate bone cements/gelatine microsphere complex is placed in three
3h is impregnated in chloromethanes, replaces a solvent per hour, removes PCL.Then it is dried in vacuo at 40 DEG C for 24 hours, uses deionized water
Cleaning 3 times is placed in drying in 37 DEG C of baking ovens and obtains porous calcium phosphate/gelatin-compounded holder for 24 hours.
The macroporous structure of porous calcium phosphate manufactured in the present embodiment/gelatine microsphere compound rest remains intact, gelatine microsphere
It is evenly distributed on rack surface and inside.It is 281 ± 21 μm that this compound rest, which has the macropore of three-dimensional communication, macropore diameter, greatly
Hole porosity is 38.01 ± 1.23%, and compression strength is 3.51 ± 1.02Mpa, and external degradation is after 28 days, gelatine microsphere part drop
Solution, leaves dispersion hole.
Embodiment 3
Select TPU (Mn=60000) as cast material is sacrificed, it is " phosphorus that natural polymer, which selects gelatin, bone cement system,
Sour four calcium+calcium monohydrogen phosphate (molar ratio 1:1) ", implementation steps include：
(1) 3D-Bioplotter is usedTMThe prefabricated TPU cylinders of printer sacrifice model：TPU is put into high temperature barrel, is selected
With the syringe needle of 300 μm of internal diameters, setting heating temperature is 220 DEG C.Utilize AutoCAD Software for Design diameter 8mm, the cylinder of high 5mm
Body Model imports Bioplotter RP delamination softwares and carries out layered shaping to it, layer height is 240 μm, then will be layered
File imports Visual Machines softwares, and setting model internal fiber stack manner is 0 ° and 90 ° and replaces successively, between fiber
Away from for 1mm.Platform temperature is adjusted after heat preservation 20min and is set as 20 DEG C, and nitrogen extrusion pressure is 2.5bar, and fiber squeezes out printing speed
Degree is 4mm/s, is then printed to obtain model.
(2) emulsion-crosslinking method prepares gelatine microsphere：The preparation that document Biomaterials 96 (2016) 33-46 is introduced
Gelatine microsphere method is improved, and the 15wt.% aqueous gelatin solutions of 20mL are slowly injected into and are heated in 50 DEG C of water-baths
In 100mL atoleine+0.5mL Span-80 mixed solutions, stirring and emulsifying 20min, then ice bath cures 20min, then slowly adds
Enter 10mL Geniposides ethanol solution [Geniposide a concentration of 0.5% (g/ml)], crosslinking is each with ice-cold petroleum ether and ethyl alcohol afterwards for 24 hours
Cleaning 3 times is sieved after freeze-drying and takes 53-106 μm of gelatine microsphere spare.
(3) calcium phosphate bone cement and microballoon compounding and pouring, molding：Gelatine microsphere is uniformly mixed with bone cement powder, it is bright
Glue microspheres amount is 5wt.%, in the ratio of 0.6mL/g by Na2HPO4-NaH2PO4Solidify liquid (0.25M Na2HPO4Aqueous solution and
0.25M NaH2P O4Aqueous solution is with volume ratio 1:1 is formulated) it is mixed with composite granule, reconcile into mixture slurry.TPU is sacrificial
Domestic animal model is placed in the mold that appearance and size matches, and mixture slurry is filled into model with perfusion tool, and appropriate pressurization makes
Slurry adequately fills up mold, is demoulded after 30min, and sample is put into 37 DEG C, 120h is conserved in the climatic chamber of 97% humidity, then
It is placed on drying in 37 DEG C of baking ovens and for 24 hours, obtains TPU/ calcium phosphate bone cements/gelatine microsphere complex.
(4) model is sacrificed in removal, obtains compound rest：TPU/ calcium phosphate bone cements/gelatine microsphere complex is placed in N,
3h is impregnated in dinethylformamide-chloroform mixed solution, replaces a solvent per hour, removes TPU.Then at 40 DEG C
Lower vacuum drying for 24 hours, clean 3 times with deionized water, is placed in dry in 37 DEG C of baking ovens and is obtained porous calcium phosphate/gelatin-compounded for 24 hours
Holder.
The macroporous structure of porous calcium phosphate manufactured in the present embodiment/gelatine microsphere compound rest remains intact, gelatine microsphere
It is evenly distributed on rack surface and inside.It is 287 ± 12 μm that this compound rest, which has the macropore of three-dimensional communication, macropore diameter, greatly
Hole porosity is 37.21 ± 1.36%, and compression strength is 2.91 ± 0.32Mpa, and external degradation is after 28 days, gelatine microsphere part drop
Solution, leaves dispersion hole.
Embodiment 4
Select PC (food-grade) as cast material is sacrificed, it is " phosphoric acid four that natural polymer, which selects gelatin, bone cement system,
Calcium+calcium monohydrogen phosphate (molar ratio 1:1) ", implementation steps include：
(1) 3D-Bioplotter is usedTMThe prefabricated PC cylinders of printer sacrifice model：PC is put into high temperature barrel, is selected
The syringe needle of 500 μm of internal diameters, setting heating temperature are 240 DEG C.Utilize AutoCAD Software for Design diameter 8mm, the cylinder of high 5mm
Model imports Bioplotter RP delamination softwares and carries out layered shaping to it, and layer height is 400 μm, then the text that will be layered
Part imports Visual Machines softwares, and setting model internal fiber stack manner is that 0 ° and 90 ° of nozzle replaces successively, fiber
Spacing is 2mm.Platform temperature is adjusted after heat preservation 20min and is set as 20 DEG C, and nitrogen extrusion pressure is 3.0bar, and fiber squeezes out printing
Speed is 4mm/s, is then printed to obtain model.
(2) emulsion-crosslinking method prepares gelatine microsphere：The preparation that document Biomaterials 96 (2016) 33-46 is introduced
Gelatine microsphere method is improved, and the 15wt.% aqueous gelatin solutions of 20mL are slowly injected into and are heated in 50 DEG C of water-baths
In 100mL atoleine+0.5mL Span-80 mixed solutions, stirring and emulsifying 20min, then ice bath cures 20min, then slowly adds
Enter 10mL Geniposides ethanol solution [Geniposide a concentration of 0.5% (g/ml)], crosslinking is each with ice-cold petroleum ether and ethyl alcohol afterwards for 24 hours
Cleaning 3 times is sieved after freeze-drying and takes 53-106 μm of gelatine microsphere spare.
(3) calcium phosphate bone cement and microballoon compounding and pouring, molding：Gelatine microsphere is uniformly mixed with bone cement powder, it is bright
Glue microspheres amount is 5wt.%, in the ratio of 0.6mL/g by Na2HPO4-NaH2PO4Solidify liquid (0.25M Na2HPO4Aqueous solution and
0.25M NaH2P O4Aqueous solution is with volume ratio 1:1 is formulated) it is mixed with composite granule, reconcile into mixture slurry.PC is sacrificed
Model is placed in the mold that appearance and size matches, and mixture slurry is filled into model with perfusion tool, and appropriate pressurization makes slurry
Body adequately fills up mold, is demoulded after 30min, and sample is put into 37 DEG C, and 120h is conserved in the climatic chamber of 97% humidity, is then put
Drying for 24 hours, obtains PC/ calcium phosphate bone cements/gelatine microsphere complex in 37 DEG C of baking ovens.
(4) model is sacrificed in removal, obtains compound rest：PC/ calcium phosphate bone cements/gelatine microsphere complex is placed in trichlorine
3h is impregnated in methane, replaces a solvent per hour, removes PC.Then it is dried in vacuo at 40 DEG C for 24 hours, is cleaned with deionized water
It 3 times, is placed in drying in 37 DEG C of baking ovens and obtains porous calcium phosphate/gelatin-compounded holder for 24 hours.
The macroporous structure of porous calcium phosphate manufactured in the present embodiment/gelatine microsphere compound rest remains intact, gelatine microsphere
It is evenly distributed on rack surface and inside.It is 486 ± 13 μm that this compound rest, which has the macropore of three-dimensional communication, macropore diameter, greatly
Hole porosity is 24.21 ± 1.36%, and compression strength is 5.21 ± 0.32Mpa, and external degradation is after 28 days, gelatine microsphere part drop
Solution, leaves dispersion hole.
Embodiment 5
PCL (Mn=45000), which is selected, as cast material, natural polymer selection chitosan, bone cement system is sacrificed is
" partially crystallized calcium phosphate+calcium monohydrogen phosphate+hydroxyapatite (mass ratio 45:45:10) ", implementation steps include：
(1) 3D-Bioplotter is usedTMThe prefabricated PCL cylinders of printer sacrifice model：PCL is put into high temperature barrel, is selected
With the syringe needle of 300 μm of internal diameters, setting heating temperature is 180 DEG C.Utilize AutoCAD Software for Design diameter 8mm, the cylinder of high 5mm
Body Model imports Bioplotter RP delamination softwares and carries out layered shaping to it, layer height is 240 μm, then will be layered
File imports Visual Machines softwares, and setting model internal fiber stack manner is that 0 ° and 90 ° of nozzle replaces successively, fine
Dimension spacing is 1mm.Platform temperature is adjusted after heat preservation 20min and is set as 4 DEG C, and nitrogen extrusion pressure is 1.6bar, and fiber extrusion is beaten
Print-out rate is 5mm/s, is then printed to obtain model.
(2) emulsion-crosslinking method prepares chitosan microball：According to document (Progress in Modern Biomedicine
Vol.16NO.15MAY.2016) method introduced prepares chitosan microball, dissolves chitosan in 3wt.% acetic acid aqueous solutions,
It is slowly injected into the 100mL atoleine+0.5mL Span-80 mixed solutions in stirring, is slow added into 10mL Geniposide ethyl alcohol
Solution [Geniposide a concentration of 2% (g/ml)] is respectively cleaned 3 times after being crosslinked 6h with petroleum ether and ethyl alcohol, and being sieved after freeze-drying takes 53-
212 μm of chitosan microballs are spare.
(3) calcium phosphate bone cement and microballoon compounding and pouring, molding：Chitosan microball is uniformly mixed with bone cement powder,
Gelatine microsphere content is 5wt.%, mixes deionized water with composite granule in the ratio of 0.5mL/g, reconciles into mixture slurry.
PCL sacrifice models are placed in the mold that appearance and size matches, mixture slurry are filled into model with perfusion tool, suitably
Pressurization makes slurry adequately fill up mold, is demoulded after 30min, and sample is put into 37 DEG C, conserves in the climatic chamber of 97% humidity
Then 72h is placed on drying in 37 DEG C of baking ovens and for 24 hours, obtains PCL/ calcium phosphate bone cements/gelatine microsphere complex.
(4) model is sacrificed in removal, obtains compound rest：PCL/ calcium phosphate cement/chitosan microsphere composites are placed in
3h is impregnated in dichloromethane, replaces a solvent per hour, removes PCL.Then it is dried in vacuo at 40 DEG C for 24 hours, uses deionization
Water cleans 3 times, is placed in drying in 37 DEG C of baking ovens and is obtained for 24 hours with porous calcium phosphate/chitosan compound rest.
The macroporous structure of porous calcium phosphate manufactured in the present embodiment/gelatine microsphere compound rest remains intact, gelatine microsphere
It is evenly distributed on rack surface and inside.It is 304 ± 13 μm that this compound rest, which has the macropore of three-dimensional communication, macropore diameter, greatly
Hole porosity is 40.21 ± 1.16%, and compression strength is 2.18 ± 0.34Mpa, and external degradation is after 28 days, chitosan microball part
Degradation, leaves dispersion hole.
Experimental example 6
TPU (Mn=60000), which is selected, as cast material, natural polymer selection chitosan, bone cement system is sacrificed is
" tetracalcium phosphate+calcium monohydrogen phosphate (molar ratio 1:1) ", implementation steps include：
(1) 3D-Bioplotter is usedTMThe prefabricated TPU cylinders of printer sacrifice model：TPU is put into high temperature barrel, is selected
With the syringe needle of 500 μm of internal diameters, setting heating temperature is 210 DEG C.Utilize AutoCAD Software for Design diameter 8mm, the cylinder of high 5mm
Body Model imports Bioplotter RP delamination softwares and carries out layered shaping to it, layer height is 400 μm, then will be layered
File imports Visual Machines softwares, and setting model internal fiber stack manner is that 0 ° and 90 ° of nozzle replaces successively, fine
Dimension spacing is 1.5mm.Platform temperature is adjusted after heat preservation 20min and is set as 20 DEG C, and nitrogen extrusion pressure is 2.5bar, and fiber squeezes out
Print speed is 4mm/s, and then printing obtains model.
(2) emulsion-crosslinking method prepares chitosan microball：According to document (Progress in Modern Biomedicine
Vol.16NO.15MAY.2016) method introduced prepares chitosan microball, dissolves chitosan in 3wt.% acetic acid aqueous solutions,
It is slowly injected into the 100mL atoleine+0.5mL Span-80 mixed solutions in stirring, is slow added into 10mL Geniposide ethyl alcohol
Solution [Geniposide a concentration of 2% (g/ml)] is respectively cleaned 3 times after being crosslinked 6h with petroleum ether and ethyl alcohol, and being sieved after freeze-drying takes 53-
212 μm of chitosan microballs are spare.
(3) calcium phosphate bone cement and microballoon compounding and pouring, molding：Chitosan microball is uniformly mixed with bone cement powder,
Gelatine microsphere content is 10wt.%, in the ratio of 0.5mL/g by Na2HPO4-NaH2PO4Solidify liquid (0.25M Na2HPO4It is water-soluble
Liquid and 0.25M NaH2P O4Aqueous solution is with volume ratio 1:1 is formulated) it is mixed with composite granule, reconcile into mixture slurry.It will
TPU sacrifices model and is placed in the mold that appearance and size matches, and mixture slurry is filled into model with perfusion tool, appropriate to add
Pressure makes slurry adequately fill up mold, is demoulded after 30min, and sample is put into 37 DEG C, conserves 120h in the climatic chamber of 97% humidity,
Then it is placed on drying in 37 DEG C of baking ovens and for 24 hours, obtains PCL/ calcium phosphate bone cements/gelatine microsphere complex.
(4) model is sacrificed in removal, obtains compound rest：TPU/ calcium phosphate cement/chitosan microsphere composites are placed in
3h is impregnated in n,N-Dimethylformamide-dichloromethane mixed solution, replaces a solvent per hour, removes TPU.Then 40
It is dried in vacuo at DEG C for 24 hours, is cleaned 3 times with deionized water, be placed in drying in 37 DEG C of baking ovens and obtained with porous calcium phosphate after drying for 24 hours
Calcium/chitosan compound rest.
The macroporous structure of porous calcium phosphate manufactured in the present embodiment/gelatine microsphere compound rest remains intact, gelatine microsphere
It is evenly distributed on rack surface and inside.It is 475 ± 22 μm that this compound rest, which has the macropore of three-dimensional communication, macropore diameter, greatly
Hole porosity is 30.21 ± 1.24%, and compression strength is 3.57 ± 0.22Mpa, and external degradation is after 28 days, chitosan microball part
Degradation, leaves dispersion hole.
Experimental example 7
Select PCL (Mn=45000) as cast material is sacrificed, it is " phosphorus that natural polymer, which selects gelatin, bone cement system,
Sour four calcium+calcium monohydrogen phosphate (molar ratio 1:1) ", implementation steps include：
(1) 3D-Bioplotter is usedTMThe prefabricated PCL cylinders of printer sacrifice model：PCL is put into high temperature barrel, is selected
With the syringe needle of 300 μm of internal diameters, setting heating temperature is 180 DEG C.Utilize AutoCAD Software for Design diameter 8mm, the cylinder of high 5mm
Body Model imports Bioplotter RP delamination softwares and carries out layered shaping to it, layer height is 240 μm, then will be layered
File imports Visual Machines softwares, and setting model internal fiber stack manner is that 0 ° and 90 ° of nozzle replaces successively, fine
Dimension spacing is 1mm.Platform temperature is adjusted after heat preservation 20min and is set as 4 DEG C, and nitrogen extrusion pressure is 1.6bar, and fiber extrusion is beaten
Print-out rate is 5mm/s, is then printed to obtain model.
(2) emulsion-crosslinking method prepares gelatine microsphere：The preparation that document Biomaterials 96 (2016) 33-46 is introduced
Gelatine microsphere method is improved, and the 15wt.% aqueous gelatin solutions of 20mL are slowly injected into and are heated in 50 DEG C of water-baths
In 100mL atoleine+0.5mL Span-80 mixed solutions, stirring and emulsifying 20min, then ice bath cures 20min, then slowly adds
Enter 10mL Geniposides ethanol solution [Geniposide a concentration of 0.5% (g/ml)], is crosslinked each with ice-cold petroleum ether and ethyl alcohol after 9h
Cleaning 3 times is sieved after freeze-drying and takes 53-106 μm of gelatine microsphere spare.
(3) calcium phosphate bone cement and microballoon compounding and pouring, molding：Gelatine microsphere is uniformly mixed with bone cement powder, it is bright
Glue microspheres amount is 5wt.%, in the ratio of 0.6mL/g by Na2HPO4-NaH2PO4Solidify liquid (0.25M Na2HPO4Aqueous solution and
0.25M NaH2P O4Aqueous solution is with volume ratio 1:1 is formulated) it is mixed with composite granule, reconcile into mixture slurry.PCL is sacrificial
Domestic animal model is placed in the mold that appearance and size matches, and mixture slurry is filled into model with perfusion tool, and appropriate pressurization makes
Slurry adequately fills up mold, is demoulded after 30min, and sample is put into 37 DEG C, conserves 72h in the climatic chamber of 97% humidity, then
It is placed on drying in 37 DEG C of baking ovens and for 24 hours, obtains PCL/ calcium phosphate bone cements/gelatine microsphere complex.
(4) model is sacrificed in removal, obtains compound rest：PCL/ calcium phosphate bone cements/gelatine microsphere complex is placed in two
It is impregnated in chloromethanes 3 hours, replaces a solvent per hour, remove PCL.Then it is dried in vacuo at 40 DEG C for 24 hours, uses deionization
Water cleans 3 times, is placed in drying in 37 DEG C of baking ovens and obtains porous calcium phosphate/gelatin-compounded holder for 24 hours.
The macroporous structure of porous calcium phosphate manufactured in the present embodiment/gelatine microsphere compound rest remains intact, gelatine microsphere
It is evenly distributed on rack surface and inside.It is 279 ± 15 μm that this compound rest, which has the macropore of three-dimensional communication, macropore diameter, greatly
Hole porosity is 38.14 ± 1.36%, and compression strength is 2.01 ± 0.22Mpa, and external degradation experiment shows gelatine microsphere 1
Degradation is complete substantially after week, leaves compared with polydispersion macropore.
Claims (10)
1. a kind of preparation method of porous calcium phosphate/natural polymer compound rest, which is characterized in that include the following steps：
（1）The prefabricated full communicating macromolecule of hole sacrifices model：It is printed with spy with high molecular material using 3D printer
Determine appearance and size and the full communicating macromolecule of internal structure, hole sacrifices model；
（2）Prepare calcium phosphate bone cement and natural polymer microballoon mixture slurry：By self-curable calcium phosphate bone cement powder and day
Right polymer microsphere is uniformly mixed, and solidify liquid is then added and reconciles uniformly, obtains calcium phosphate bone cement and natural polymer microballoon
Mixture slurry；
（3）Mixture slurry and maintenance is perfused：By step（1）The macromolecule of preparation is sacrificed model and is put into match with appearance and size
In matching die, then step（2）The calcium phosphate bone cement of preparation is fed into high score with natural polymer microballoon mixture slurry
Son is sacrificed in model, and slurry is made to fill up the hole of model, is conserved after demoulding, is dry, is obtained macromolecule and is sacrificed model/calcium phosphate bone
Cement/natural polymer microballoon composite curing body；
（4）It removes macromolecule and sacrifices model：Step（3）The macromolecule of acquisition sacrifices model/calcium phosphate bone cement/natural polymer
Sub- microballoon composite curing body, which is placed in organic solvent, to be impregnated, and is removed macromolecule and is sacrificed model, and then dry, washing, re-dry obtain
To porous calcium phosphate/natural polymer compound rest of three-dimensional communication.
2. preparation method according to claim 1, which is characterized in that step（1）The high molecular material, which is selected, to be gathered in oneself
One or more blends in ester, makrolon, polyurethane, polyhydroxyalkanoate and polylactic acid.
3. preparation method according to claim 1, which is characterized in that step（1）The macromolecule sacrifices the structure of model
Parameter is：Fibre diameter is 200-600 μm, and fiber spacing is 1-2 mm, by adjusting fibre diameter and spacing, by pore size
Control is 100-1700 μm.
4. preparation method according to claim 1, which is characterized in that step（2）The calcium phosphate bone cement powder and day
So the mass ratio of polymer microsphere is（90-99）：（1-10）；The calcium phosphate bone cement and natural polymer microballoon mixture slurry
Liquid-solid ratio be 0.4-0.7mL/g.
5. preparation method according to claim 1, which is characterized in that step（2）The calcium phosphate bone cement is phosphoric acid four
Calcium+dicalcium phosphate dihydrate, unformed calcium phosphate+dicalcium phosphate dihydrate, tetracalcium phosphate+type alpha tricalcium phosphate+calcium monohydrogen phosphate, part are tied
Brilliant calcium phosphate+calcium monohydrogen phosphate+hydroxyapatite, calcium monohydrogen phosphate+type alpha tricalcium phosphate+calcium carbonate and tetracalcium phosphate-calcium monohydrogen phosphate body
Any one in pastern bone cement.
6. preparation method according to claim 1, which is characterized in that step（2）The natural polymer microballoon raw material is
It is one or more in gelatin, chitosan, glucan, polyaminoacid and collagen.
7. preparation method according to claim 1, which is characterized in that step（2）The natural polymer microballoon is using breast
Change cross-linking method to be prepared, be crosslinked as cross-linking agent solution using Geniposide, crosslinking time is 6-24 h；The natural polymer
The grain size of microballoon is 53-212 μm.
8. preparation method according to claim 1, which is characterized in that step（4）The organic solvent is dichloromethane, three
Chloromethanes, tetrahydrofuran, ethyl acetate are one or more in n,N-Dimethylformamide and butanone.
9. a kind of porous calcium phosphate/natural polymer composite support obtained by claim 1 ~ 8 any one of them preparation method
Frame, which is characterized in that the macro porosity led of the porous calcium phosphate/natural polymer compound rest is 25%-45%, aperture 200-
600 μm。
10. a kind of porous calcium phosphate/natural polymer compound rest described in claim 9 is applied in bone defect healing.
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