CN104353121A - BMP microsphere loaded 3D printing porous metal stent and preparation method thereof - Google Patents
BMP microsphere loaded 3D printing porous metal stent and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of biomedical materials, and particularly relates to a BMP microsphere loaded 3D printing porous metal stent and a preparation method thereof. According to the invention, a loaded microsphere-containing three-dimensional micro-stent is built in each hole of a 3D printing titanium stent. The problem that in the prior art, because the diameter of a hole is overlarge, cells only can be subjected to climbed growth on the two-dimensional space of the wall of the hole, and difficult to be subjected to three-dimensional hierarchical growth in the whole hole is solved, and by filling the three-dimensional micro-stent with a rhBMP-2 or rhBMP-7 loaded chitosan microsphere, a better growth and differentiation environment is provided for cells, thereby further promoting the combination of bone tissues and the stent. The three-dimensional micro-stent provided by the invention makes the complete healing of numerous patients with bone tissue defect caused by illnesses and accidents and the like possible; the three-dimensional micro-stent can also be used as a novel interbody fusion instrument, and applicable to an interbody fusion surgery, therefore, the three-dimensional micro-stent has an important clinical application value.
Description
Technical field
The present invention relates to technical field of biomedical materials, be specifically related to a kind of three-dimensional micro rack containing load microsphere and preparation method thereof.
Background technology
Titanium and titanium alloys, owing to having excellent mechanical property and biocompatibility, is widely used in clinical medicine Bone Defect Repari and bone implantation field.But the elastic modelling quantity of fine and close titanium and titanium alloys, far above people's bone modulus, easily causes " stress shielding " effect, cause the problems such as osteonecrosis, distortion and implant loosen.Porous titanium and titanium alloys, owing to having unique pore structure, has the performance matched with the skeleton sclerous tissues be replaced, can effectively weaken or the screen effect that eliminates stress.Therefore, porous titanium and titanium alloys has broad application prospects, and becomes current research focus.But the influence factor of traditional porous metal material preparation technology is too much, flow process is complicated, cannot one-shot forming, and ubiquity pore structure can not accurately control, internal void is communicated with the problems such as rate variance.
3D prints the process by scan-datas such as CT, built by Computer Design, titanium alloy can be printed as the personalized porous meeting demand and be communicated with labyrinth, not only provide space to Bone Ingrowth, also because loose structure reduces the elastic modelling quantity of titanium alloy, achieve and the mating of normal bone tissues elastic modelling quantity, and not mating of degradation time and body demand need not be worried, become the important directions that 3D is printed on orthopaedics development.
But, 3D prints porous titanium alloy support itself does not but have biological activity, do not have the site that cell can identify, and current various 3D on the market prints porous titanium alloy material, aperture is usually larger, diameter is about 300-1500um, for the average 20-30um diameter of cell, obviously too spacious, cell can only seek connections with growth on its hole wall two-dimensional space, the growth of three-dimensional level in whole hole can not be realized, and then also cannot realize sufficient bone amount of growing in support.
The invention in each hole of POROUS TITANIUM, build a three-dimensional micro rack containing load microsphere, by giving the propagation of cell, differentiation provides a good environment.In this individual system, POROUS TITANIUM structure is only responsible for providing mechanical strength, three-dimensional micro rack then provides optimal cell growth environment, the design having abandoned metal rack in traditional view must meet the restriction in the most applicable Growth of Cells aperture, be prepared into macroscopic void and high porosity structure as far as possible, thus achieved the maximization of the minimized of metal and Bone Ingrowth amount; Interior three-dimensional micro rack is then no longer by the restriction first meeting mechanical strength, adopt the material being beneficial to osteogenesis most as far as possible, build short texture, there is cell recognition site, be applicable to the three-dimensional bionic micro rack that cell seeks connections with growth, for cell offers the best growth microenvironment, thus the mutual supplement with each other's advantages both realizing.
In addition, the support implanted merely often can not meet clinical needs, cause bone grafting failure, this is because after stenter to implant human body, its centre nutrient substance is under-supply, and partial pressure of oxygen is low, the seed cell growth in centre, propagation, differentiation and the needs of skeletonization can not be met, cause seed cell to stop growing even dead, bone-forming effect is lost, and its basic reason is that tissue engineered bone self-bone grafting effect is not strong; In addition, the bone-forming effect of support is not good enough is also the major reason that restriction artificial bone scaffold develops.For this reason, have studied three kinds of methods both at home and abroad and solve its ossified activity: one adopts associational cells to cultivate, by cultured cells and artificial bone scaffold compound, dissimilar cell is carried out Mixed culture, there is by iuntercellular the Growth and Differentiation that meticulous mutual regulation relationship promotes cell.The advantage that associational cells is cultivated is that living cells can promote bone-forming effect, but complex operation, cultivation cycle is long, and clinical being not easy to is promoted.Another method adopts microsurgery to promote its self-bone grafting effect exactly, mainly contains forward purchasing vascularized fascia lobe parcel artificial bone, vascular pedicle muscle flap parcel artificial bone scaffold at present.Shortcoming also clearly, is exactly first need row forward purchasing operation, adds the misery of patient.Also have a kind of method to adopt cell growth factor to promote its self-bone grafting effect exactly, method is easy, and clinical being easy to is promoted.Comparatively speaking, artificial bone scaffold activity of ossify has clinical practice advantage significantly to adopt cell growth factor to promote.
Better to osteoblast differentiation, can promote that osseous tissue combines with support by inducing mesenchymal stem cell in the present invention after making three-dimensional micro rack implantable bone tissue, inventor has prepared the three-dimensional micro rack of a kind of carried medicine sustained-release.The medicine controlled release carrier that described carried medicine sustained-release three-dimensional micro rack employing chitosan microball etc. are good, rhBMP-2 etc. have the stronger osteoinductive activity factor, make the microsphere of slow release, then microsphere is filled in three-dimensional rack with holes by collagen, the three-dimensional micro rack of carried medicine sustained-release of preparation is that cell provides better growing environment, promotes that osseous tissue combines with support further.
Instant invention overcomes the drawback of prior art, provide the three-dimensional micro rack of a kind of carried medicine sustained-release, improve now standoff performance, numerous osseous tissue defect patient caused due to the reason such as disease, accident is cured completely and becomes possibility, bring hope to increasing patient, there is important clinical value.
Summary of the invention
The object of the present invention is to provide a kind of support containing load microsphere, described support comprises metal rack, the three-dimensional micro rack being filled in the metal rack inside that 3D prints and the load microsphere be filled in three-dimensional micro rack that 3D prints.
Further, by CT image is imported three-dimensional imaging software, obtain the 3-D view of targeted bony tissue, set up the threedimensional model of loose structure in a computer, 3D prints obtained metal rack; Preferred Mimics or CAS of three-dimensional imaging software.Preferably, obtain the 3-D view of targeted bony tissue, with average Kong Zhuwei 100-1000um, aperture for 300-3000um, with regular hexahedron, the filling of regular dodecahedron structural units, expand this image, obtain personalized porous and be communicated with three-dimensional digital model.The regular dodecahedron structural units filling that preferably apertures post is 300um, aperture is 1500um, expand this image, obtain personalized porous and be communicated with three-dimensional digital model.The obtained metal rack of described 3D printing is selected from one or more in porous pure titanium support, porous pure magnesium bracket, porous titanium alloy support, porous tantalum niobium alloy, preferred POROUS TITANIUM support.
The gel that described three-dimensional micro rack is formed by gelatin solution, hydroxyapatite forms.Described hydroxyapatite powder is preferably nanometer hydroxyapatite powder.
Further, hydroxyapatite is replaced by calcium phosphate, calcium sulfate, polyester (polyesters), polydioxanone (polydioxanone), one or more of poly-fumaric acid two hydroxypropyl acrylate (propylene fumarate, PPF), poe (polyorthoesters), polyanhydride (polyanhydrides) and polyurethane (polyurethanes) etc.
Further, gelatin be replaced by collagen, glycosaminoglycan, fibrin, real silk, chitosan, sodium alginate, hyaluronic acid one or more.
Further, add in the mixed liquor of gelatin solution, hydroxyapatite formation using glutaraldehyde solution or EDC/NHS as cross-linking agent.
Load microsphere i.e. " loaded article " is connected " loaded article-carrier conjugates " prepared with microsphere supported.Can improve and the transhipment in vivo of control load thing and metabolism, realize slow release and the orientation of attachment, improve bioavailability and therapeutic index.
Further, described " loaded article " is selected from one or more cells and/or one or more medicines and/or one or more somatomedin and/or one or more genes.
Described cell be selected from following in one or more: chondrocyte, marrow stromal cell, epithelial cell, endotheliocyte, mesenchymal stem cells MSCs.
The described factor be selected from following in one or more: somatomedin: TGF β, epidermal growth factor (EGF), platelet derived growth factor (PDGF), nerve growth factor (NGF), angiogenesis factor (VEGF), colony stimulating factor (CSF), hepatocyte growth factor, insulin like growth factor, placental growth factor); Differentiation factor; Cytokine, such as interleukin is (as IL1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20 or IL-21, often kind or α or β), interferon (such as IFN-α, IFN-β and IFN-γ), tumor necrosis factor (TNF), IFN-γ inducible factor (IGIF), bone morphogenetic protein(BMP) (BMP); Chemotactic factor (as MIPs (macrophage inflammatory protein), such as MIP1 α and MIP1 β; MCPs (monocyte chemoattractant protein), such as MCP1,2 or 3; RANTES (activation of regulation and control Normal T-cell expression and secretion)) and trophic factors.Such as, somatomedin can be selected from TGF-β 1, TGF-β 2, TGF-β 3, TGF-β 4, any other member of TGF-β 5 or TGF-beta superfamily comprises Activins, inhibin class, and bone morphogenetic protein(BMP) comprises BMP1, BMP2, BMP3, the group of BMP4, BMP5, BMP6, BMP7 composition.
Described medicine be selected from following in one or more: infection, analgesic medicine, cancer therapy drug, promotion knitting medicine, the medicine that prevents bone from dissolving.Further, described medicine is selected from: Cefoxitin, amphiphilic enzyme element, neomycin, mupirocin, polymyxin B, antifungal agent, caye promise ketone, conventional analgesics (acetaminophen, tramadol, codeine, nefopam etc.), nonsteroidal anti-inflammatory (NSAID), AINS (ketone ibuprofen, indomethacin), morphine derived product one or more.
In general, main carrier mass comprises: the polymer of (1) natural origin, as the polymer etc. of collagen, fibrin, hyaluronic acid, Semen sojae atricolor or algae derivant, chitosan, hydroxylated alkane.In the non-mineral matter composition of mammiferous connective tissue and bone, collagen is modal protein, and has certain status in cellular infiltration and repair in trauma.Alginate are a kind of polysaccharide at a large amount of non-immunogenic existed in Sargassum surface, because it has gelling properties, use wider in organizational project.Chitosan (chitosan) is a kind of positively charged polysaccharide be prepared from by acetylglucosamine (N-acetyl-D-glucosamine) and chitinous N-deacetylation, and it is because having good biocompatibility, sequestering and degradability and famous.Hyaluronic acid is another kind of natural polymer, play an important role in repair in trauma, hyaluronic acid and derivant thereof are studied on a large scale in biomedical and organizational project are applied, and its form has the subcutaneous injection viscose glue in gel, sponge, implant and eye surgery.Fibrin is exactly a kind of protein relevant with blood coagulation, Fibrin Glue is the fibrin clot utilizing the reaction of Fibrinogen and thrombin to make to have Qiang great Dot to make a concerted effort, itself there is the effect promoting that blood capillary is formed, can the healing of acceleration of wound.Other natural polymers have gelatin, glucosan, cellulose etc.(2) inorganic substances and pottery, as hydroxyapatite, tricalcium phosphate and sulfate, also has bio-vitric and metal etc.Hydroxyapatite (hydroxyapatite, HA) there is bone conductibility, can bonding direct with bone formation, from 1970, be widely used as clinical bone alternate material, wherein only have cavernous hydroxyapatite to be developed as support is as the slow-released carrier (microgranule, powder, granule, thin slice and block) of BMPs.Calcium phosphate bone cement in inorganic material, pottery and coating are proved to be as multi-functional carrier, be developed as implantable and injectable carrier, they can in vivo in-situ solidifying and can be used for transmit biological activity somatomedin (avoiding the degeneration of protein under cryogenic), there is significant bone-forming effect.Bioactivity glass a kind ofly has hard, based on fine and close silicon bioactive substance, the bone conduction good because of it and bone merge performance can directly and bone formation bonding, research finds the bone formation of bio-vitric bootable local in a large number in vitro, the effect of BMPs can be increased in vivo, supporting osteoblastic growth, promoting osteoblastic differentiation by stimulating the synthesis (carrying out labelling with alkali phosphatase, type i collagen and osteocalcin) of phenotype.(3) synthetic biodegradable polymers, as the copolymer and biodegradation material pla-pcl etc. of polylactic acid, polyglycolic acid and their copolymer, polyglycolic acid and Polyethylene Glycol; Polylactic acid, also known as polylactide, is that its catabolite is lactic acid, can participate in internal metabolism directly by the single polymer containing the polylactic acid molecule dehydrating condensation of carboxyl and hydroxyl.(4) combine various material or other biological molecule composite carrier.
Preferred chitosan microball load bone morphogenetic protein(BMP).Preferred, chitosan microball load rhBMP-2 or rhBMP-7.
According to different reaction mediums and architectural characteristic, the preparation method of chitosan microball can be divided into emulsifying-cross-linking method, complex coacervation, spray drying method and emulsion solvent evaporation technique etc.In addition, multi-emulsion method, film emulsion process, pH value is also had to regulate the method such as method, ultrasonic-immersion-polishing.
Emulsifying-cross-linking method
Emulsifying-cross-linking method joins in the oil phase containing emulsifying agent by the dilute acid soln of chitosan, w/o type emulsion is obtained by modes such as mechanical agitation, ultrasonic or even phase emulsifyings, add a certain amount of cross-linking agent again, cross-linking agent is diffused in aqueous phase, by chitosan crosslinked one-tenth microsphere, after filtration, solvent wash, drying obtain final chitosan microball.
Complex coacervation
Coacervation is also known as the sedimentation method, in the dilute acid soln of chitosan, slowly drip the precipitant of anion while stirring, as sodium alginate, sodium carboxymethylcellulose etc., reduce the dissolubility of chitosan, after continuing to stir a period of time, namely chitosan microball separates out from dilute acid soln.Complex coacervation utilizes two kinds of high molecular polymers with opposite charges and chitosan to interact with interionic to be cross-linked to form complex microsphere, and the dissolubility of material reduces, and separate out in solution, co-precipitation becomes microsphere.This kind of method is without the need for machine solvent, and the microsphere carrying drug ratio of preparation is high.
Spray drying method
Spray drying method is that be atomized into small drop, then contact with the thermal current of inertia, in drop, moisture and solvent flash evapn form chitosan microball by chitosan solution through spraying.Chitosan microball prepared by spray drying method is mainly as pharmaceutical carrier.The method preparation is quick, repeatable high, but chitosan microball is often in loose structure, and micromolecular drug release is too fast, add chitosan solution through high-temperature process, easily make medicine degeneration or solvent explosion danger, therefore, spray drying method is not generally suitable for slow releasing pharmaceutical system.
Emulsion solvent evaporation technique
Emulsion solvent evaporation technique, also known as Oil-phase drying, is preparing w/o type emulsion or O/W/C) after type emulsion, by the organic solvent in heating or decompression method removing chitosan solution, microsphere is solidified, also can carry out chemical crosslinking to microsphere after the solvent evaporates.
Preferred, 3D prints POROUS TITANIUM support; The three-dimensional micro rack that internal stent is filled is formed by the hydroxyapatite of NTx and Nano grade, is filled in three-dimensional micro rack by the chitosan microball of load rhBMP-2 or rhBMP-7 by collagen.
Further, obtain having porous loose structure containing the three-dimensional micro rack of load microsphere, average diameter is 50-100 μm.
Another object of the present invention is the preparation method providing a kind of three-dimensional micro rack containing load microsphere, and described preparation method comprises:
1) CT image is imported three-dimensional imaging software, obtain the 3-D view of targeted bony tissue, set up the threedimensional model of loose structure in a computer;
2) according to step 1) in three dimensional model printing support;
3) by after gelatin deionized water dissolving, the chitosan microball that bag is loaded with loaded article is joined in collagen solution, then adding nano-hydroxy limestone flour, to form concentration be the concentration of 5-10mg/ml, is cross-linking agent, fully mixed by above mixed liquor with EDC/NHS;
4) by step 3) mixed liquor that obtains is added drop-wise on support, and carries out lyophilization, obtains the three-dimensional micro rack of load microsphere.
Further, described preparation method also comprises, and after obtaining the three-dimensional micro rack containing load microsphere, the three-dimensional micro rack containing load microsphere is carried out sterilizing, independent subpackage process.Preferably the three-dimensional micro rack containing load microsphere is put into Epoxyethane sterilizing box and carry out sterilizing.
Further, after gelatin deionized water dissolving, be mixed with the concentration of 0.5-20g/ml, the chitosan microball that bag is loaded with loaded article is joined in collagen solution by 1-20mg/ml.
Preferably, the preparation method of a kind of three-dimensional micro rack containing load microsphere provided by the invention, described preparation method comprises:
1) CT image is imported the three-dimensional imaging software such as Mimics or CAD, obtain the 3-D view of targeted bony tissue, average Kong Zhuwei 100-1000um, aperture are 300-3000um, with regular hexahedron, the filling of regular dodecahedron structural units, expand this image, obtain personalized porous and be communicated with three-dimensional digital model;
2) adopting EOS M280 metal material 3D printer, with titanium alloy (Ti-6Al-4V) for raw material, printing POROUS TITANIUM support according to designing a model;
3) by after gelatin deionized water dissolving, be mixed with the concentration of 0.5-20g/ml, then chitosan microball bag being loaded with rhBMP-2 or rhBMP-7 joins in collagen solution by 1-20mg/ml, adding nano-hydroxy limestone flour formation concentration is again the concentration of 5-10mg/ml, take EDC/NHS as cross-linking agent, above mixed liquor is fully mixed;
4) by step 3) mixed liquor that obtains is added drop-wise on support, and carries out lyophilization, obtains the three-dimensional micro rack of load microsphere;
5) above-mentioned three-dimensional micro rack is put into Epoxyethane sterilizing box and carry out sterilizing, independent subpackage process.
The object of the invention is to also provide above-mentioned three-dimensional micro rack at bone defect healing and bone interface (bone-bone; Bone-support) fusion in application.When three-dimensional micro rack load cells and/or medicine and/or somatomedin and/or gene, described three-dimensional micro rack can also be used for the recurrence that prevents disease, and eases the pain, and is conducive to bone and recovers heavy burden function early, promotes neurological functional recovery, improves the quality of living.
Accompanying drawing explanation
Fig. 1. the POROUS TITANIUM support printed according to three-dimensional digital model
Fig. 2. the three-dimensional micro rack of load microsphere
Fig. 3. the three-dimensional micro rack electron-microscope scanning figure (3000 ×) of load microsphere
Detailed description of the invention
Below in conjunction with specific embodiment, setting forth the present invention further, only for explaining the present invention, and can not limitation of the present invention be interpreted as.Those having ordinary skill in the art will appreciate that: can carry out multiple change, amendment, replacement and modification to these embodiments when not departing from principle of the present invention and aim, scope of the present invention is by claim and equivalents thereof.The experimental technique of unreceipted actual conditions in the following example, the usually conveniently conditioned disjunction condition examinations of advising according to manufacturer.
Embodiment 1 prepares the three-dimensional micro rack of titanium alloy-gelatin/HA
Prepare the three-dimensional micro rack of titanium alloy-gelatin/HA:
1) CT image is imported Mimics or CAS three-dimensional imaging software, obtain the 3-D view of targeted bony tissue, the regular dodecahedron structural units filling being 1500um with Kong Zhuwei 300um, aperture, expand this image, obtain personalized porous and be communicated with three-dimensional digital model;
2) adopt EOS M280 metal material 3D printer, taking titanium alloy as raw material, printing POROUS TITANIUM support (see Fig. 1) according to designing a model;
3) by after bovine collagen deionized water dissolving, be mixed with the concentration of 1g/ml, then chitosan microball bag being loaded with rhBMP-2 joins in collagen solution by 5mg/ml, adding nano-hydroxy limestone flour formation concentration is again the concentration of 5-10mg/ml, be cross-linking agent with EDC/NHS, above mixed liquor is fully mixed;
4) the chitosan microball collagen solution that step 3 is obtained is added drop-wise on support, and carries out lyophilization, obtain the three-dimensional micro rack (see Fig. 2) of load microsphere;
5) above-mentioned support is put into Epoxyethane sterilizing box and carry out sterilizing, independent subpackage process.
The sign of the three-dimensional micro rack of embodiment 2
1, the mensuration of three-dimensional micro rack porosity
Improvement liquid displacement method is adopted to measure the porosity of artificial bone scaffold.In graduated cylinder, insert volume is V1 dehydrated alcohol, three-dimensional artificial bone holder material is put into graduated cylinder, negative pressure-pumping air after Smin, anhydrous alcohol is riddled in the space of timbering material completely, record volume is now VZ, then is Vs by material taking-up record alcohol by volume at this moment.Calculate the porosity of three-dimensional bionic artificial bone scaffold as follows:
Porosity=(V1-V3)/(V2-V3) × 100%
2, three-dimensional micro rack mechanics property analysis
Omnipotent mechanics machine is adopted to measure the Compressive Mechanical Properties of timbering material.With BAM artificial bone in contrast.Loading velocity is 5mm/min, and the maximum pressure that timbering material flattens is F (N), according to formula P=F/A (A is compression area), tries to achieve comprcssive strength.Elastic modelling quantity is tried to achieve according to formula E=σ/ε.(σ is stress, and ε is strain).
The results are shown in Table 1.
The sign of the three-dimensional micro rack of table 1
| Theoretical value | Measured value | |
| Kong Zhu (um) | 300 | 291±30 |
| Porosity (%) | 80.5 | 74±5 |
| Highly (mm) | 15.0 | 14.5±0.04 |
| Elastic modelling quantity (GPa) | 1.8 | 3.6±0.8 |
| Comprcssive strength (MPa) | -- | 86.4±12.9 |
Result shows, and three-dimensional micro rack comprcssive strength prepared by the present invention and elastic modelling quantity, close to normal person's bone, effectively avoid stress shielding, are conducive to better fusion; High porosity, reaches 80%, is more conducive to osteocyte and grows into wherein.
3, the scanning electron microscopic observation of three-dimensional micro rack
Get the timbering material of above preparation, under being placed on scanning electron microscope to its surface, bottom surface and the process of internal structure spray platinum respectively (Electronic Speculum brand FEI model: Nova NanoSEM 450), different accelerating potential, amplifies different multiples and observes.Fracture after immersing liquid nitrogen material, its internal structure of electron-microscope scanning, and choose 3 high power fields at material internal, observes and can see there is the adhesion of microsphere (specifically seeing Fig. 3) on the surface of support.
Claims (13)
1. a three-dimensional micro rack, described support comprises metal rack, the three-dimensional micro rack being filled in the metal rack inside that 3D prints and the load microsphere be filled in three-dimensional micro rack that 3D prints.
2. three-dimensional micro rack according to claim 1, is characterized in that, described metal rack is selected from one or more in porous pure titanium support, porous pure magnesium bracket, porous titanium alloy support, porous tantalum niobium alloy.
3. three-dimensional micro rack according to claim 1, is characterized in that, described three-dimensional micro rack is made up of gelatin solution, nanometer hydroxyapatite.
4. three-dimensional micro rack according to claim 1, is characterized in that, the loaded article in described load microsphere is selected from one or more cells and/or one or more medicines and/or one or more somatomedin and/or one or more genes.
5. three-dimensional micro rack according to claim 4, is characterized in that, described cell be selected from following in one or more: chondrocyte, marrow stromal cell, epithelial cell, endotheliocyte, mesenchymal stem cells MSCs; The described factor be selected from following in one or more: somatomedin, cytokine, differentiation factor, chemotactic factor, MCPs monocyte chemoattractant protein, RANTES and trophic factors; Described medicine be selected from following in one or more: infection, analgesic medicine, cancer therapy drug, promotion knitting medicine, the medicine that prevents bone from dissolving.
6. three-dimensional micro rack according to claim 4, it is characterized in that, the described factor be selected from following in one or more: TGF β, epidermal growth factor EGF, platelet derived growth factor PDGF, nerve growth factor, angiogenesis factor VEGF, colony stimulating factor CSF, hepatocyte growth factor, insulin like growth factor, placental growth factor; Interleukin, interferon, TNF, IFN-γ inducible factor IGIF, bone morphogenetic protein(BMP) BMP; MIPs macrophage inflammatory protein.
7. three-dimensional micro rack according to claim 1, it is characterized in that, described microsphere be selected from the polymer of natural origin, inorganic substances and pottery, synthetic biodegradable polymers or combine various material or other biological molecule composite carrier in one or more.
8. three-dimensional micro rack according to claim 1, is characterized in that, described microsphere be selected from following in one or more: collagen, hyaluronic acid, Semen sojae atricolor or algae derivant, the polymer of hydroxylated alkane, chitosan, gelatin, glucosan, cellulose; Hydroxyapatite, tricalcium phosphate, sulfate, bio-vitric; Copolymer, the biodegradation material pla-pcl of polylactic acid, polyglycolic acid and their copolymer, polyglycolic acid and Polyethylene Glycol.
9. three-dimensional micro rack according to claim 1, is characterized in that, described load microsphere is the chitosan microball of load rhBMP-2 or rhBMP-7.
10. three-dimensional micro rack according to claim 1, is characterized in that, described three-dimensional micro rack has porous loose structure, and average diameter is 50-100 μm.
The preparation method of 11. 1 kinds of three-dimensional micro racks, is characterized in that, described preparation method comprises:
1) CT image is imported three-dimensional imaging software, obtain the 3-D view of targeted bony tissue, set up the threedimensional model of loose structure in a computer;
2) according to step 1) in three dimensional model printing support;
3) by after gelatin deionized water dissolving, the load microsphere that bag is loaded with loaded article is joined in collagen solution, adding nano-hydroxy limestone flour again, to form concentration be the concentration of 5-10mg/ml, and to add EDC/NHS be that cross-linking agent carrys out cross-linked gelatin, fully mixed by above mixed liquor;
4) by step 3) mixed liquor that obtains is added drop-wise on support, and carries out lyophilization, obtains the three-dimensional micro rack of load microsphere.
12. preparation methoies according to claim 10, it is characterized in that, in described preparation method after the molten deionized water dissolving of gelatin, be mixed with the concentration of 0.5-20g/ml, the chitosan microball then bag being loaded with loaded article rhBMP-2 or rhBMP-7 joins in collagen solution by 1-20mg/ml.
Three-dimensional micro rack described in 13. claim 1-10 any one or the application of preparation method in bone defect healing described in claim 11-12 any one.
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