CN103055352B - Calcium phosphate/collagen composite biologic ceramic material and preparation method thereof - Google Patents
Calcium phosphate/collagen composite biologic ceramic material and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a CaP (Calcium Phosphate)/collagen composite biologic ceramic material and a preparation method thereof. The composite biologic ceramic is prepared by adopting a porous calcium phosphate ceramic as the substrate and I-type collage as the toughening reinforcing phase in a vacuum negative pressure pouring and crosslinking mode. The process is as follows: firstly, preparing the first type through porous calcium phosphate ceramic, wherein the porosity is 60-95%; dipping the porous calcium phosphate ceramic into a collagen solution of which the concentration is 5-20mg/ml; and vacuuming to 0-10Pa at normal temperature and pouring, keeping the pressure for 1-3 hours and carrying out ultrasonic oscillation. The vacuum negative pressure pouring process can be repeated according to demands. The calcium phosphate ceramic poured with the collagen is frozen and dried to prepare the composite biologic ceramic after being subjected to crosslinking. The prepared biologic ceramic has good biocompatibility and biological activity, and at the same time has a mechanical strength better than that of a pure calcium phosphate ceramic material, so that the biologic ceramic can be used as artificial bones and bone tissue engineering bracket materials, and has wide clinical application prospects in orthopedics.
Description
Technical field
The present invention relates to compound bioceramic material of a kind of porous calcium phosphate ceramic and collagen protein and preparation method thereof, belong to field of biomedical materials.
Background technology
Calcium phosphate biological ceramic material (Calcium Phosphate Bioceramics, CaP), because it has the inorganic constituents similar with body bone tissue, and has both multiple good biological characteristics and is widely used as bone renovating material.Common series of calcium phosphate bioceramic material comprises hydroxyapatite (Hydroxyapatite, HA), β phase tricalcium phosphate (beta-Tricalcium phosphate, β-TCP) and their complex biophasic calcium phosphate ceramic (Biphasic calcium phosphate, BCP) etc.Existing studies confirm that, porous calcium phosphate is that bioceramic possesses the required biological characteristics of numerous bone renovating materials, as biocompatibility, bone conduction and bone inducibility, biodegradable absorption etc.Their forms with granule or small blocks in clinical are widely used in the reparation filling that non-bearing position bone is damaged; yet because it can not meet the application requirements of heavy burden bone defect repair aspect mechanical property, so this type of bioceramic material remains a difficult point urgently to be resolved hurrily for the reparation of bearing position osseous tissue.Guaranteeing on the basis of the good biology performance of calcium phosphate biological ceramic material, further improve its mechanical property, in conjunction with organism internal skeleton structural stress environment, the new bone formation of rapid induction final reconstruction defect osseous tissue are to be expected to solve the desirable approach that bearing position bone defect repair is rebuild.
Desirable load bone reparing biological material should have both good biology performance and mechanical property simultaneously.Biology performance mainly wishes that it has good biocompatibility, bone conductibility, osteoinductive and osteogenesis ability.Mechanical property comprises resistance to compression, bending strength, and a plurality of aggregative indicatores such as elastic modelling quantity can approach or match with the mechanical property of nature bone to greatest extent.Existing research thinks, the composition of material, interface and micropore structure have decisive action to the bone inducibility of calcium phosphate ceramic.Clinical research confirmation, although most of calcium phosphate ceramic shows good biological characteristics, can be well and human body hard tissue and soft tissue bio-compatible, but result of study shows dense calcium phosphate ceramics and can not effectively induce the formation of new bone tissue simultaneously, the calcium phosphate ceramic only with loose structure just possesses bone induction generative capacity.Required related gene and the albumen of the new osteogenesis of can adsorb in its microscopic void/enrichment after in porous calcium phosphate ceramic implantable bioartificial body, promote the generation of new capillary vessel tissue simultaneously, and early stage vascularization can provide the required nutrient condition of skeletonization and carry metabolite, be beneficial to osteoblastic Differentiation and proliferation, and then the generation of induction new bone tissue.Therefore, microcellular structure is most important to the osteoinductive of series of calcium phosphate bioceramic material and osteogenesis ability.Based on this, existing Patents technology (method of preparing porous structure ceramic artificial bone, the patent No.: CN1903384; The porous bio-ceramic of controllable microstructure, its preparation method and application, the patent No.: CN 1268583C) preparation of calcium phosphate porous structure and optimization are reported.Obviously, due to the intervention of pore structure and the fragility feature of calcium phosphate ceramic self, will certainly reduce the mechanical property of this type of material, thus restriction reparation application as load osseous tissue by this type of bioceramic material.Therefore there is technology report to pass through Material cladding technology to improve the mechanical property of ceramic material.For example patent CN1935270A has reported and a kind ofly take hydroxyapatite as matrix, diopside and aluminium oxide are composite bioceramic material and the technology of preparing thereof of toughened and reinforced body, and composite boilogical ceramic prepared by this technology has than mechanical properties such as the better fracture toughness of pure HA, bending strengths.
The main component of nature bone comprises inorganic calcium phosphate and organic collagen protein, and wherein inorganic calcium phosphate be take the apatite of biomineralization and is main (Biological apatite), in bone containing the biological phosphorus lime stone of 60～75 mass percents of having an appointment.Collagen protein (Collagen) is a kind of natural polymer, and it is the main organic principle of human body skin and bone, is the rich in protein of content in bone matrix.Collagen protein has good biocompatibility and low immunity, is suitable as the substrate that new osteocyte attaches growth, is a kind of ideal material for bone tissue restoration.Existing research is recently devoted to exploitation and is prepared collagen-base or using it as adding the reparation of the biomaterial of phase as osseous tissue.A kind of mineralized collagen is disclosed in foreign patent WO 93/12736 as the method for bone tissue restoration.But it is only applicable to non-bearing position osseous tissue repair in trauma.
Characteristic based on series of calcium phosphate bioceramic and shortcoming, the object of the present invention is to provide a kind of method of preparing calcium phosphate and collagen protein composite biological material.Composite prepared by the present invention can improve the mechanical property of bioceramic, and the composition of the further analog bone substrate of energy, using this type of pottery as bone tissue restoration timbering material, to there is the function of good mechanical property and induced tissue regeneration, be expected to promote the reconstruction application of bearing position osseous tissue.
Summary of the invention
The object of the present invention is to provide a kind of calcium phosphate and collagen protein composite biological material.
The present invention is achieved through the following technical solutions:
A calcium phosphate/collagen albumen composite bioceramic material, is composited by porous calcium phosphate ceramic and collagen protein.
As optimal way, this composite boilogical ceramic be take porous calcium phosphate ceramic as matrix, and collagen protein is toughened and reinforced phase, and the mass percent of each raw material (Wt%) is: calcium phosphate ceramic 80%～98%, collagen protein 2～20%.
As optimal way, described porous calcium phosphate ceramic pore structure characteristic is that ceramic overall porosity is 60%～95%, and macropore diameter is 100～500 microns, has micropore mutually to connect between macropore, and macropore inwall is covered with capillary micropore.
As optimal way, described porous calcium phosphate ceramic adopts hydrogen peroxide foaming or microsphere occupy-place method or slip casting method preparation, and ceramic material composition is: hydroxyapatite, β phase tricalcium phosphate or biophasic calcium phosphate ceramic.
As optimal way, described collagen protein is I-collagen type.
As optimal way, described collagen protein forms three-dimensional collagen fabric network structure in ceramic hole.
The preparation method that another object of the present invention is to provide a kind of above-mentioned calcium phosphate/collagen albumen composite bioceramic material, its operating procedure comprises:
(a) prepare IPN and connect porous calcium phosphate ceramic: prepare ceramic porous structure idiosome, then through sintering porcelain into.
(b) perfusion: preparation collagen solution, the porous ceramics with preparation in collagen solution submergence step (a), carries out priming by vacuum under room temperature, then, product is carried out to ultrasonic wave concussion stirring.
(c) crosslinked: the calcium phosphate ceramic of perfusion collagen protein to be cross-linked through physics or chemical method, finally product to be carried out to lyophilization.
As optimal way, idiosome described in step (a) adopts hydrogen peroxide foaming or microsphere occupy-place method or slip casting method preparation, and the temperature of described sintering is 1000～1200 ℃; Collagen solution concentration described in step (b) is 5～20 mg/ml, described priming by vacuum process is for being evacuated to 0～10 Pa, pressurize 1～3 hour, described priming by vacuum and sonic oscillation process can repeat as required, and the time that described concussion is stirred is 5～20 minutes; Cross-linking method described in step (c) is crosslinked (the J Mech Behav Biomed of genipin, 2012,15:176-189.), UV-crosslinked (J Biomed Mater Res. 1995,29 (11): 1373-1379), cross-linking radiation (Radiat Res. 1964,22 (4): 606-621), glutaraldehyde cross-linking (J Mater Sci-Mater M, 1995, a kind of 6:460-472), described cryodesiccated temperature is-60 ℃～-20 ℃, and the time is 24～48 hours.
The present invention also provides a kind of purposes of described calcium phosphate/collagen albumen composite bioceramic material: used as the damaged reparation of human body hard tissue or scaffold material of bone tissue engineering.Particularly use it for bearing position osseous tissue repair in trauma.
Beneficial effect of the present invention:
1, the composition of Simulation of Composite natural bone substrate of the present invention, had both significantly improved the mechanical property of bioceramic, had promoted again its bone tissue restoration regeneration function.In biomedical sector, there is huge application prospect, in particular for the damaged repair and reconstruction of sclerous tissues, in os osseum defect, as repairing filling bracket material, induce rapidly the generation of new bone tissue, strengthen bone connection and healing function.
2, the porous calcium phosphate ceramic that described composite material by adopting has sintered porcelain into is as matrix, between its macropore, there is micropore mutually to connect, macropore inwall is covered with capillary micropore, this structure makes composite have good osteoinductive and osteogenesis ability on the one hand, be conducive on the other hand hold more collagen protein, make it enter material internal, and form tridimensional network.
3, in described composite, collagen protein is cross-linked with each other and forms three-dimensional collagen fabric network structure in ceramic hole, this structure is conducive to improve the mechanical property of material on the one hand, promote toughened and reinforced effect, form sealed with the loose structure of ceramic matrix material on the other hand, make both combinations more firm, material is more stable, is also conducive to cell tactophily on it simultaneously.
4, adopt I-collagen type.Collagen protein is a kind of GL-PP, contains a small amount of half lactic acid and glucose, is the main component of extracellular matrix, is also one of most important composition in human body simultaneously.It is extensively present among the tissues such as skin, skeleton, muscle, cartilage, joint of human body.Wherein in human body os osseum tissue, mainly have I-collagen type, it plays the multi-efficiencies such as support, protection and reparation.I-collagen type is mainly by fibroblast or as synthetic in osteoblast with the similar cell in its source, and it is promoting osteocyte propagation, differentiation, and there is important biological effect induction osteanagenesis reconstruction aspect.
5, in the preparation method of composite of the present invention, by negative pressure of vacuum, pour into the collagen protein of certain viscosity, realize the compound of porous ceramics and collagen protein, whole technique is physics recombination process, without chemical reaction and organic solvent, participate in, avoided preparation technology to admix the pollution of poisonous and harmful substances to bioceramic at home and abroad.By ultrasonic wave concussion and repeat to be perfused with to be beneficial to and improve collagen protein loading, make it adsorb equably simultaneously and be filled among ceramic hole.Cross-linking process is conducive to collagen protein and forms the netted structure of three-dimensional fiber.
Accompanying drawing explanation
Fig. 1 is preparation technology's flow chart of the present invention;
Fig. 2 is portioned product figure prepared by the present invention, and totally 3 groups, every group of two samples, are respectively tricalcium phosphate/collagen protein composite ceramics, biphasic calcium phosphate/collagen protein composite ceramics and hydroxyapatite/collagen albumen composite ceramics from left to right;
Fig. 3 is the SEM shape appearance figure of calcium phosphate/collagen albumen composite ceramic material in embodiment, wherein the SEM shape appearance figure of (a) micro-pure ha porous ceramics; (b) be the SEM shape appearance figure of the biological material of embodiment 1 hydroxyapatite/collagen albumen composite ceramics; (c) be the SEM shape appearance figure of the biological material of embodiment 2 tricalcium phosphates/collagen protein composite ceramics; (d) be the SEM shape appearance figure of the biological material of embodiment 3 biphasic calcium phosphates/collagen protein composite ceramics;
Fig. 4 is the Mechanics Performance Testing figure of calcium phosphate/collagen albumen composite bioceramic material;
Fig. 5 is biphasic calcium phosphate/collagen protein composite ceramic material Marrow Mesenchymal Stem Cells In Vitro (MSCs) laser co-focusing displaing micro picture, and wherein (a) is cell seeding 1 day; (b) be cell seeding 3 days; (c) be cell seeding 7 days; (d) be cell seeding 21 days.
The specific embodiment
Below in conjunction with accompanying drawing, technique of the present invention is described in further detail.
Preparation technology's flow process of the present invention as shown in Figure 1.Raw-material preparation is divided into two aspects, the preparation of the calcium phosphate ceramic body of the suitable hole of the first, and it two is that the preparation of type i collagen protein solution is prepared.The applicable calcium phosphate ceramic of the present invention mainly comprises following three classes: hydroxyapatite (Hydroxyapatite, HA), tricalcium phosphate (beta-Tricalcium phosphate, β-TCP), and biophasic calcium phosphate ceramic (Biphasic calcium phosphate, BCP), the making of the porous ceramic bodies relating to can be via hydrogen peroxide foaming (Chinese patent: CN1903384), microgranule occupy-place method (Chinese patent: CN 1268583C), slip casting method (United States Patent (USP): No.3090094) or additive method prepare porous ceramics idiosome, then the porous calcium phosphate ceramic forming through calcining.The pottery that the embodiment of the present invention is used is prepared idiosome by hydrogen peroxide foaming, and ceramic overall porosity is 60%～95%, and macropore diameter is 100～500 microns, has micropore mutually to connect between macropore.The applicable collagen protein of the present invention is all kinds collagen protein, and the embodiment of the present invention is used through sterilizing, purification, gone the present invention that demonstrates of the first type calf cow leather collagen of immune terminal amino acid.The collagen content using in complex ceramic body is 5～20% mass percents, by the concentration of 5～20 mg/ml, prepares use collagen solution.
Following classified as several most preferred embodiments of the present invention, it should be understood that these embodiment, only for the object of illustration, never limit the scope of the invention.
embodiment 1
Take hydroxyapatite powder as raw material, the cuboid porous calcium phosphate ceramic product of preparation 5 * 5 * 20 mm.Holes of products gap structure requires: whole porosity 85% ± 5%, macropore diameter are that 400 ± 50 μ m, IPN perforation micropore size are 80 ± 20 μ m.Concrete steps are as follows:
1) by standard model sieve for the hydroxyapatite powder making through Wet Method Reaction, filtering out diameter is the hydroxyapatite dry powder of 80～160 μ m, adopt subsequently hydrogen peroxide foaming to prepare porous ceramics idiosome, 100 ℃ of oven dry of low temperature <;
2) ceramic idiosome is put into Muffle furnace sintering, from room temperature, with the speed of 5 ℃/min, be warming up to 1100 ℃ and continue 2 hours sintering, then furnace cooling.To obtain the cuboid that Porous Hydroxyapatite Ceramic cuts into 5 * 5 * 20 mm subsequently;
3) by through sterilizing, purification, remove the I-type calf cow leather collagen of immune terminal amino acid, with deionized water, dilute and by the concentration preparation collagen solution of 5 mg/ml;
4) the collagen solution submergence porous ceramics to prepare, room temperature is evacuated to < 10 Pa and pours into, pressurize 3 hours, then stir 10 minutes through ultrasonic wave concussion, repeat evacuation negative pressure filling process once.
5) pottery of perfusion collagen protein is cross-linked to 48 hours with the genipin of 10 mg/ml, then with-20 ℃ of temperature lyophilizations 24 hours.
The scanning electron microscope picture of the hydroxyapatite/collagen albumen composite bioceramic material of gained as shown in Figure 3, through universal testing machine, recording its maximum compressive strength is that 8.7 MPa(method of testings are referring to GB/T 1964-1996), compared with 3.1 times of pure ha porous bio-ceramic material lift.
embodiment 2:
Take porous beta-calcium phosphate ceramics as matrix, prepare tricalcium phosphate/collagen protein (TCP/Collagen) composite ceramic material.Ceramic integral porosity 85% ± 5%, macropore diameter are that 400 ± 50 μ m, IPN perforation micropore size are 80 ± 20 μ m, and all the other product preparation process and step are identical with embodiment 1.The scanning electron microscope picture of tricalcium phosphate/collagen protein composite bioceramic material of gained as shown in Figure 3, through universal testing machine, recording its maximum compressive strength is 5.4 MPa, compared with the mechanical property of the porous beta-calcium phosphate ceramics material before composite collagen, promote approximately 2.9 times, than low 3.8 MPa of comprcssive strength of hydroxyapatite/collagen albumen (HA/Collagen) composite ceramics in embodiment 1, this is because the mechanical property of pure phosphoric acid DFP pottery own is just poor than pure ha pottery.
embodiment 3
Take porous biophasic calcium phosphate ceramic as matrix, prepare biphasic calcium phosphate/collagen protein (BCP/Collagen) composite ceramic material.Ceramic integral porosity 85% ± 5%, macropore diameter are that 400 ± 50 μ m, IPN perforation micropore size are 80 ± 20 μ m, and all the other product preparation process and step are identical with embodiment 1.The scanning electron microscope picture of biphasic calcium phosphate/collagen protein composite bioceramic material of gained as shown in Figure 3, through universal testing machine, recording its maximum compressive strength is 6.7 MPa, compared with the mechanical property of the porous biophasic calcium phosphate ceramic material before composite collagen, promote approximately 3.0 times, comprcssive strength than hydroxyapatite/collagen albumen (HA/Collagen) composite ceramics in embodiment 1 is low, but the comprcssive strength than tricalcium phosphate/collagen protein (TCP/Collagen) composite ceramics in embodiment 2 is high, this be because the mechanical property of pure phosphoric acid calcium pottery under the same conditions, its mechanical strength sequence is: HA > BCP > TCP.
embodiment 4
Other condition and technique are with embodiment 1, it is compound that difference is to adopt the hydroxylapatite ceramic of different pore structures to be that matrix carries out collagen protein perfusion, and its ceramic porosity 95% ± 5%, macropore diameter are that to connect micropore size be 100 ± 20 μ m for 500 ± 100 μ m, IPN.It is 8.2 MPa that the hydroxyapatite/collagen albumen composite bioceramic material of gained records maximum its comprcssive strength through universal testing machine, compared with the mechanical property of the hydroxylapatite ceramic material before composite collagen, promote approximately 2.9 times, but compared with low 0.5 MPa of comprcssive strength of the hydroxyapatite/collagen albumen composite ceramics of gained in embodiment 1, the porous skeleton structure of this presentation of results calcium phosphate ceramic has important function aspect the mechanical property of composite.Although the increase in ceramic integral porosity and aperture, promoted the increase of collagen content in composite, when increasing because of its porosity and aperture, sacrificed the mechanical strength of material itself, thereby the mechanical property of the material after finally compound declines to some extent compared with embodiment 1.
embodiment 5
Other condition and technique is with embodiment 1, and it is compound that difference is to adopt the collagen protein of variable concentrations to pour into, and its collagen concentration is 20 mg/ml, and through crosslinked 72 hours of genipin.The hydroxyapatite/collagen albumen composite bioceramic material of gained, through universal testing machine, recording its maximum compressive strength is 9.1 MPa, comparatively the mechanical property of composite collagen pre-ceramic material promotes approximately 3.3 times, and in this presentation of results calcium phosphate ceramic pore structure, compound more collagen protein is conducive to the lifting of the final mechanical property of material.
embodiment 6
To after biphasic calcium phosphate/collagen protein composite ceramic material sterilizing of embodiment 3 preparations, cultivate altogether in vitro 3 weeks with mesenchymal stem cells MSCs (MSCs), respectively when cultivating 1 day, 3 days, 7 days and 21 days, adopt diacetic acid fluorescein/propidium iodide (FDA/PI) to dye to cell, then adopt confocal laser scanning microscope and take pictures, result shows (as shown in Figure 5), cell is attached at the growth of pottery/collagen inwall, and differentiation on this material, propagation are obviously.Material has induction osteanagenesis and speeds the function that bone defect repairing is rebuild.
With method of the present invention, the calcium phosphate/collagen albumen composite bioceramic material of preparing, has greatly promoted the mechanical property of pure phosphoric acid calcium porous ceramic film material.Collagen protein after crosslinked, in ceramic hole, be three-dimensional collagen fabric network structure, give the enough mechanical strengths of material and toughness, by the composition of composite collagen analog bone substrate, make material there is good biocompatibility and biological activity simultaneously.
The foregoing is only the preferred embodiments of the present invention, is only illustrative for the purpose of the present invention, and nonrestrictive; Those of ordinary skills understand, and in the spirit and scope that limit, can carry out many changes to it in the claims in the present invention, revise, and even equivalence change, but all will fall into protection scope of the present invention.
Claims (9)
1. a calcium phosphate/collagen albumen composite bioceramic material, it is characterized in that, take porous calcium phosphate ceramic as matrix, collagen protein is toughened and reinforced phase, wherein the mass percent of collagen protein (wt%) is 5～20%, described porous calcium phosphate ceramic pore structure characteristic is that ceramic overall porosity is 60%～95%, macropore diameter is 100～500 microns, between macropore, there is micropore mutually to connect, macropore inwall is covered with capillary micropore, the toughened and reinforced three-dimensional collagen fabric network structure forming in described ceramic hole after priming by vacuum and ultrasonic wave concussion stir and be crosslinked for collagen solution mutually of described collagen protein, the bionical natural bone tissue composition of described composite bioceramic material, there is good osteoinductive and osteogenesis ability.
2. composite bioceramic material according to claim 1, it is characterized in that, described porous calcium phosphate ceramic adopts hydrogen peroxide foaming or microsphere occupy-place method or slip casting method preparation, and ceramic material composition is: hydroxyapatite, β phase tricalcium phosphate or biophasic calcium phosphate ceramic.
3. composite bioceramic material according to claim 1, is characterized in that, described collagen protein is I-collagen type.
4. a preparation method for calcium phosphate/collagen albumen composite bioceramic material as claimed in claim 1, is characterized in that, its operating procedure comprises:
(a) prepare IPN and connect porous calcium phosphate ceramic: prepare ceramic porous structure idiosome, then through sintering porcelain into;
(b) perfusion: preparation collagen solution, the porous ceramics with preparation in collagen solution submergence step (a), carries out priming by vacuum under room temperature, then, product is carried out to ultrasonic wave concussion stirring;
(c) crosslinked: the calcium phosphate ceramic of perfusion collagen protein to be cross-linked through physics or chemical method, finally product to be carried out to lyophilization.
5. the preparation method of calcium phosphate/collagen albumen composite bioceramic material according to claim 4, it is characterized in that, idiosome described in step (a) adopts hydrogen peroxide foaming or microsphere occupy-place method or slip casting method preparation, and the temperature of described sintering is 1000～1200 ℃; Collagen solution concentration described in step (b) is 5～20 mg/ml, described priming by vacuum process is for being evacuated to 0～10 Pa, pressurize 1～3 hour, described priming by vacuum and sonic oscillation process are at least carried out once, and the time that described concussion is stirred is 5～20 minutes; Cross-linking method described in step (c) is that genipin is crosslinked, a kind of in cross-linking radiation, glutaraldehyde cross-linking, and described cryodesiccated temperature is-60 ℃～-20 ℃, and the time is 24～48 hours.
6. the preparation method of calcium phosphate/collagen albumen composite bioceramic material according to claim 5, is characterized in that, described cross-linking radiation is specially ultraviolet light irradiation cross-linking.
7. a purposes for calcium phosphate/collagen albumen composite bioceramic material as claimed in claim 1, is characterized in that, uses it for and makes the damaged repair materials of human body hard tissue.
8. the purposes of calcium phosphate/collagen albumen composite bioceramic material according to claim 7, is characterized in that, uses it for making scaffold material of bone tissue engineering.
9. the purposes of calcium phosphate/collagen albumen composite bioceramic material according to claim 7, is characterized in that, uses it for and makes bearing position osseous tissue repair in trauma material.
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| US8758791B2 (en) * | 2010-01-26 | 2014-06-24 | Warsaw Orthopedic, Inc. | Highly compression resistant matrix with porous skeleton |
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| US3090094A (en) * | 1961-02-21 | 1963-05-21 | Gen Motors Corp | Method of making porous ceramic articles |
| EP0361896A3 (en) * | 1988-09-29 | 1991-01-23 | Collagen Corporation | Method for improving implant fixation |
| CN1647826A (en) * | 2005-02-01 | 2005-08-03 | 翁文剑 | Medical beta phase tricalcium phosphate/collagen cmposite material and its preparing method |
| CN101530634A (en) * | 2009-04-21 | 2009-09-16 | 昆明医学院第一附属医院 | Bionic dual-phase ceramic-like biologically active bone and manufacturing method thereof |
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