CN101461963B - Multiplex composite bone tissue engineering bracket material capable of degrading gradiently and preparation method thereof - Google Patents
Multiplex composite bone tissue engineering bracket material capable of degrading gradiently and preparation method thereof Download PDFInfo
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- CN101461963B CN101461963B CN200910036479A CN200910036479A CN101461963B CN 101461963 B CN101461963 B CN 101461963B CN 200910036479 A CN200910036479 A CN 200910036479A CN 200910036479 A CN200910036479 A CN 200910036479A CN 101461963 B CN101461963 B CN 101461963B
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Abstract
The invention discloses a multiplex composite engineering scaffold material capable of gradually decomposing bone tissue and a preparation method thereof. The composite scaffold material consists of calcium phosphate bone cement, biological compatible degradable synthetic high polymer and biological compatible degradable natural high polymer, has better mechanical property and gradient degradation characteristic, and can achieve the aim of regenerating and repairing bone tissue defect by implanting a bone growth factor to induce in-vivo stem cells to be differentiated into bone cells, thereby obviously improving initial strength and toughness of the scaffold material, and ensuring enough strength and toughness of the scaffold material during operating and implanting. After compounded with the high polymer material, the scaffold has excellent flexibility, so that the scaffold can be subjected to certain machining, such as cutting and the like.
Description
Technical field
The invention belongs to the tissue engineering material technology of biomedical engineering field, particularly multiplex composite bone tissue engineering bracket material capable of degrading gradiently and preparation method thereof.
Background technology
Numerous because of the damaged case of bone that industrial accident, vehicle accident, orthopaedics inflammation, bone tumor and the orthopaedic disease relevant with old-age group etc. are caused, had a strong impact on people's health level and quality of life.The damaged clinical treatment method of the bone of current employing mainly contains: autologous bone transplanting, allogenic bone transplantation and artificial material reparation.Though from the body bone is ideal bone grafting material, supply the bone source limited, second operation can bring misery to the patient, and donor is produced new damage, supplies the bone district also form and dysfunction possibly occur; Though the allograph bone source is abundanter, but store in advance, easy to use; But there is immune rejection in it; And because of the careless omission of allograph bone processing aspect also possibly cause receptor to infect, and the possibility that causes communicate illness and tumor to generate is arranged, also limited the extensive use of allograph bone; Repair and adopt artificial material to carry out damaged directly the substituting of bone, owing to be difficult to realize the osteanagenesis of defect, repairing effect is undesirable.Therefore, people seek the damaged biological reconstruction restorative procedure of better bone always.
The development of tissue engineering (Tissue Engineering), treatment and the reparation damaged for bone provide comparatively ideal a, feasible approach.The core of organizational project is: set up the three dimensions complex of cell and biomaterial, promptly have the biological tissue of vitality, be used for that disease is decreased tissue and carry out the reconstruction of form, 26S Proteasome Structure and Function and reach permanent substituting.Organizational project comprises three key factors: signaling molecule (somatomedin, inducible factor), timbering material and target cell.Timbering material occupies critical role in making up engineered tissue or organ; Be not merely specific cell support structure is provided; Help exchange, cell proliferation and the differentiation of the sticking of cell, nutrient substance and move to internal stent; For the cell growth provides suitable external environment condition, and can also play the effect of template, guide tissue regeneration and control organizational structure.Ideal tissue engineering bracket material should have the loose structure of three-dimensional communication, and excellent biological compatibility with the degradation speed that tissue regeneration is complementary, can promote the chemical surface of tissue regeneration and certain mechanical strength.
Tissue engineering bracket material commonly used at present comprises the active inorganic material of degradable biological, natural biological macromolecule and degradable synthesized polymer material and their composite.The natural biological macromolecular material is representative with collagen, gelatin, chitosan, and this type material has excellent biological compatibility and cellular affinity, wide material sources; But this type material product character is unstable, most of poor mechanical property, and processing and forming is restricted; Molecular structure is complicated; In addition, degraded and absorbed is too fast, and controlled degradation property is bad; Degradable synthesized polymer material is representative with polylactic acid (PLA), polyglycolic acid (PGA) and their copolymer (PLGA); This type material has the good mechanical performance mostly; Can use multiple processing method to be prepared into three-dimensional porous material, can carry out certain designed and regulation and control to its degradation rate, active group kind etc. through MOLECULE DESIGN, but the hydrophobicity of this type material be stronger; Cellular affinity is undesirable; And it is acid that catabolite generally is, and is prone to cause aseptic inflammation, and tissue is caused bad influence; Inorganic material is representative with calcium phosphate pottery and bioactivity glass, and this type material composition is near sclerous tissues, and biocompatibility and biological activity are good; The good mechanical properties of DB aspect the bone implant material of hard tissue substituting, the better application prospect is being arranged, but this type material is fragility; On the three-dimensional communication support of preparation high porosity, acquire a certain degree of difficulty; And the intensity of its high porosity support is very low usually, in addition, owing to lack the supplied reactive activity group of similar macromolecular material; On the binding bioactive molecule, receive certain restriction, its controlled degradation property is also not ideal.Though the research of related organization's engineering scaffold material was a lot of in recent years, do not develop a kind of ideal bone tissue engineering stent material so far as yet.How preparing the high porosity support that biocompatibility, cellular affinity, good mechanical properties and material degradation and cell are grown or BFR matees basically is present Tissue Engineering Study urgent problem.One of feasible way of dealing with problems is compound through two kinds or above Biodegradable material with complementary characteristic, and carries out Bionic Design, simulation and experiment, the composite organization engineering stent material by using that processability is excellent.
Calcium phosphate bone cement (CPC) is a kind of novel type bioactive materials admittedly certainly, have excellent biological compatibility, bone conductibility, degradability, plasticity, and the heat that reaction produces is few, is that comparatively ideal bone substitutes and repair materials.Because self-curable calcium phosphate aquation at normal temperatures becomes weak crystalline hydroxy apatite, has good degradable absorbability, and is easy to molding and pore-forming, therefore be the ideal material of preparation calcium phosphate porous tissue engineering scaffold.People such as Xu have carried out systematic research to tetracalcium phosphate-calcium phosphate dibasic anhydrous system bone cement tissue engineering bracket; Cell in vitro cultivation to support shows that the calcium phosphate bone cement material has excellent biological compatibility [H.H.K.Xu; Et al.Biomaterials 2005,26:1337-1348.].Yet in years of researches and application process, the calcium phosphate material is fragility, the intensity problem of lower fails to be well solved always, has limited its extensive use.This has directly caused the porous calcium phosphate tissue engineering bracket intensity of high porosity very low.In order to solve this difficult problem, people start with from different angles and study, comprising: adopt different calcium phosphate formula systems, adding can play the additive of potentiation etc.; Select for use organic and inorganic solution such as citric acid (sodium), malic acid, sodium ascorbyl phosphate as distiller liquor; In addition, use for reference traditional Enhancement Method, compound with whisker, high-molecular organic material, short fiber etc.Make the mechanical property of calcium phosphate bone cement obtain raising in various degree through these methods, but effect is still undesirable, especially for the calcium phosphate tissue engineering bracket material with high porosity, poor mechanical property remains and hinders its actual key in application.Research at present is more, effect is preferably the method that adopts composite high-molecular material; Xu etc. have studied respectively directly and in the bone cement matrix, to have added the absorbable suture fiber [H.H.K.Xu et al.J.Biomed.Mater.Res.Part A.2005; 75:966-975.], [H.H.K.Xu et al.J.Biomed.Mater.Res.Part A.2004 to add the netted reinforce of PLGA; 69:267-278.], add chitosan [H.H.K Xu et al.Biomaterials 2005; 6:1337-1348.], improve the mechanical property of bone cement, make the mechanical property of porous bone cement support obtain apparent in view raising.Yet because the degraded of the macromolecular material that adds is obviously fast than calcium phosphate bone cement, in case with the blended at random enhancing body degraded of bone cement after, the intensity of support can significantly descend, and possibly make material can't bear the load of originally being born and subsides.On the other hand, these reinforcing agents are to the biocompatibility and the not improvement effect of cellular affinity of support, even (like the PLGA) that have also can make the biocompatibility of support and cellular affinity descend.
The regulation and control problem of timbering material degradation rate is not generally considered in the research of relevant self-curable calcium phosphate tissue engineering bracket material.
Summary of the invention
In order to overcome the weak point of above-mentioned prior art; The object of the present invention is to provide a kind of multiplex composite bone tissue engineering bracket material capable of degrading gradiently and preparation method thereof; This compound support frame material is made up of calcium phosphate bone cement, bio-compatible degradable synthesized polymer and bio-compatible degradable natural macromolecule, and after implanting, degrading, very fast natural polymer is at first degraded and original position formation connection macrovoid in compound rest; The confession new bone tissue is grown into, and plays the effect of support; The relatively slow synthetic high polymer of degrading is strengthened calcium phosphate porous support matrix attached to the hole wall of porous support, makes support can in a period of time, keep good intensity.Along with the degraded gradually of synthetic high polymer and calcium phosphate bone cement porous matrix, cell is grown into organizing constantly, and final whole compound rest is degraded fully, and implant site is substituted by freshman bone tissue.The MULTIPLE COMPOSITE timbering material has mechanical property and gradient degradation property preferably, simultaneously can also differentiation of stem cells be an osteoblast in the skeletal growth factor inductor through being written into, reach the purpose of the damaged Regeneration and Repair of osseous tissue, and can adapt to the requirement of clinical use.
The object of the invention is realized through following technical proposals: a kind of method for preparing of multiplex composite bone tissue engineering bracket material capable of degrading gradiently comprises the steps:
(1) the bio-compatible degradable synthesized polymer material is dissolved in the solvent, is mixed with mass percent concentration and is 1～20% solution, stirred then or leave standstill 1～48 hour, filter, obtain the synthetic high polymer solution A; In course of dissolution, can adopt the method for heating (40～80 ℃) to promote the synthesized polymer material dissolving as required;
Bio-compatible degradable natural macromolecular material is dissolved in the solvent, is mixed with mass percent concentration and is 5～25% solution, stirred then or leave standstill 1～48 hour, filter, obtain the natural polymer solution B; In course of dissolution, can adopt the method for heating (30～100 ℃) to promote the natural macromolecular material dissolving as required;
(2) with overall porosity be 70～95% calcium phosphate bone cement porous support 30～100 ℃ dry 1～48 hour down; The calcium phosphate bone cement porous support is dipped in the synthetic high polymer solution A that step (1) prepared; Vacuum drying 0.5～5 hour; Synthetic high polymer solution is filled in the hole of calcium phosphate bone cement porous support under pressure and capillary force action, has obtained pouring into the calcium phosphate bone cement porous support of synthesized polymer material;
Said calcium phosphate bone cement porous support can prepare with reference to following method: and method 1 (H.H.K.Xu, S.Takagi, J.B.Quinn, et al.J.Biomed.Mater.Res., 2004,68A:725-734.); Method 2 (A.Almirall, G.Larrecq, J.A.Delgado, et al.Biomaterials, 2004,25:3671-3680); Method 3 (X.Miao, Y.Hu, J.Liu, et al.Materials Letters, 2004,58:397-402); Method 4 (X.P.Qi, J.D.Ye, Y.J.Wang.J Biomed Mater Res Part A, DOI:10.1002/jbm.a.32054, inpress).
The calcium phosphate bone cement porous support that (3) will pour into synthesized polymer material was wiped away and is done the surface ,-60～-4 ℃ of following pre-freezes 1～48 hour; Freezed the composite lyophilization 2～48 hours with what obtain, dry back macromolecule forms rete on the porous calcium phosphate hole wall, promptly get the compound multi-porous tissue engineering supporting material of synthetic high polymer and calcium phosphate.Can change film forming thickness through the concentration that changes macromolecular solution as required.
(5) will be dipped in the natural polymer solution B of step (1) by resultant synthetic high polymer of step (3) and the compound multi-porous tissue engineering supporting material of calcium phosphate; Vacuum drying 0.5～5 hour; Natural polymer solution is filled in the hole of calcium phosphate bone cement porous support under pressure and capillary force action, has obtained pouring into the calcium phosphate bone cement porous support of natural polymer solution;
The calcium phosphate bone cement porous support that (6) will pour into natural polymer solution was wiped away and is done the surface ,-60～-4 ℃ of following pre-freezes 1～48 hour; Then with the frozen material lyophilization that obtains 2～48 hours; Dry back natural polymer is filled in by in resultant synthetic high polymer of step (3) and the compound multi-porous tissue engineering supporting material hole of calcium phosphate with porous or RF, promptly gets multiplex composite bone tissue engineering bracket material capable of degrading gradiently.
In order to realize the present invention better, described bio-compatible degradable synthesized polymer material comprises in polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid/polyglycolic acid copolymer (PLGA), polylactic acid/starch blend, polycaprolactone (PCL) or polycaprolactone (the PCL)/starch blend etc. any one or two or more.
Described bio-compatible degradable natural macromolecular material comprises in collagen, gelatin, chitosan, fibroin albumen, sodium alginate or the cellulose derivative etc. any one or two or more material.
The solvent that said bio-compatible degradable synthesized polymer material is dissolved in the solvent comprises 1,4-dioxane, acetone, dichloromethane, chloroform, dimethyl sulfoxide or trichloroacetic acid etc.
The solvent that said bio-compatible degradable natural macromolecular material is dissolved in the solvent is deionized water, distilled water, aqueous acetic acid, phosphate aqueous solution, dehydrated alcohol and aqueous solution thereof, calcium chloride solution or acetone etc.
Described calcium phosphate bone cement comprises unformed calcium phosphate (ACP)+dicalcium phosphate dehydrate (DCPD) system bone cement, tricalcium phosphate (TCP)+dicalcium phosphate dehydrate (DCPD) system bone cement, type alpha tricalcium phosphate (α-TCP)+dicalcium phosphate dehydrate (DCPD)+calcium carbonate (CaCO
3)+hydroxyapatite (HA) system bone cement, type alpha tricalcium phosphate (α-TCP)+dicalcium phosphate dehydrate (DCPD)+calcium carbonate (CaCO
3)+hydroxyapatite (HA)+magnesium phosphate (Mg
3(PO
4)
2)+hydrogen phosphite sodium (NaHSO
3) system bone cement, tetracalcium phosphate (TTCP)+calcium phosphate dibasic anhydrous (DCPA)+calcium carbonate (CaCO
3) system bone cement, bata-tricalcium phosphate (β-TCP)+tetrasodium pyrophosphate (Na
4P
2O
7) system bone cement or partially crystallized calcium phosphate (PCCP)+calcium phosphate dibasic anhydrous (DCPA) system bone cement.
But a kind of MULTIPLE COMPOSITE gradient degraded calcium phosphate bone tissue engineering rack is prepared from through above-mentioned method for preparing.
Compared with prior art, the present invention's tissue engineering bracket material of being used for the damaged Regeneration and Repair of osseous tissue has following characteristics and advantage:
1, the prepared multiplex composite bone tissue engineering bracket material capable of degrading gradiently of the present invention compoundly constitutes by calcium phosphate bone cement, synthetic high polymer, natural polymer are triple; Can significantly improve the early strength and the toughness of timbering material, ensureing in operation and implantation process medium-height trestle material has enough intensity and toughness; And, because the good pliability that the composite high-molecular material after-poppet has can be carried out certain machinings such as cutting.
2, the prepared multiplex composite bone tissue engineering bracket material capable of degrading gradiently of the present invention is after implanting; Because it is the fastest to be filled in the intrapore degradable natural macromolecular material of calcium phosphate bone cement porous support degradation speed; The degradation speed of the synthetic polymeric membrane on the porous calcium phosphate hole wall is relatively slow; And the degraded of bone cement is the slowest, so the degraded of MULTIPLE COMPOSITE timbering material is three kinds of gradient processes that composition material is degraded gradually wherein.Because the gradient of natural polymer and synthesized polymer material degraded; Though can descending, the intensity of timbering material can significantly not descend suddenly and subside; And along with progressively growing into of new bone can keep the good intensity of the whole maintenance of implant site, the degraded of compound support frame material has better matching property with new growing into of bone.
3, the prepared multiplex composite bone tissue engineering bracket material capable of degrading gradiently of the present invention is after implanting, and natural macromolecular material degraded back forms the loose structure that is communicated with in timbering material, for the growth of cell and tissue provides the space.And because natural polymer wherein is porous or RF, degraded is fast, directly cultured cell on support.
4, the prepared multiplex composite bone tissue engineering bracket material capable of degrading gradiently of the present invention is after implanting, and natural polymer wherein can play the remarkable effect that improves the cellular affinity of support before degraded fully.And, can in natural polymer, introduce somatomedin as required, induce In vitro culture or intravital differentiation of stem cells, give support bone inducing function, promote the growth of new bone.
5, to be used for the method for preparing scope of application of multiplex composite bone tissue engineering bracket material capable of degrading gradiently of the damaged Regeneration and Repair of bone extensive in the present invention, and technology is simple.
The specific embodiment
Below in conjunction with embodiment the present invention is described in further detail, but embodiment of the present invention is not limited thereto.
Embodiment one
1, polylactic acid/polyglycolic acid copolymer (PLGA) is dissolved in the dichloromethane, is made into the solution of 10% mass percent concentration, with magnetic stirrer 6 hours, obtain polylactic acid/polyglycolic acid copolymer solution, it is for use to put into container.
2, select for use overall porosity to be about 80%; The tetracalcium phosphate (TTCP) of pore size 200～400 μ m+calcium phosphate dibasic anhydrous (DCPA) system calcium phosphate bone cement porous support; Above-mentioned calcium phosphate bone cement porous support is put into vacuum drying oven, and 50 ℃ of following vacuum dryings 6 hours take out; Be soaked in polylactic acid/polyglycolic acid copolymer (PLGA) solution of step 1 preparation; Put into vacuum desiccator, evacuation 2 hours, polylactic acid/polyglycolic acid copolymer (PLGA) solution is filled in the hole of calcium phosphate bone cement porous support under pressure and capillary force action.
3, the calcium phosphate bone cement porous support that has poured into PLGA in the hole is taken out; Wipe away dried surface with filter paper; Put into-18 ℃ of refrigerator precoolings 24 hours; Lyophilization 24 hours under-40 ℃ of conditions afterwards, once-combined calcium phosphate porous support be the compound multi-porous tissue engineering supporting material of synthetic high polymer and calcium phosphate.
4, chitosan being dissolved in percent by volume is in 2% the dilute acetic acid aqueous solution, is mixed with mass percent concentration and is 15% chitosan solution, with magnetic stirrer 2 hours, filters, and obtains chitosan solution, for use.
5, the once-combined calcium orthophosphate base porous support of step 3 preparation is dipped in the chitosan solution that step 4 prepares; Put into vacuum desiccator; Evacuation 0.5 hour; Chitosan solution is filled in the hole of once-combined calcium phosphate porous support under pressure and capillary force action, has obtained pouring into the calcium phosphate bone cement porous support of chitosan solution.
The calcium phosphate bone cement porous support that 6, will pass through PLGA and chitosan MULTIPLE COMPOSITE is that the porous support that step 5 makes takes out, and wipes away with filter paper and does the surface, puts into-18 ℃ of pre-freezes 12 hours; With the material lyophilization that obtains 48 hours, promptly get multiplex composite bone tissue engineering bracket material capable of degrading gradiently.The final porosity of prepared multiplex composite bone tissue engineering bracket material capable of degrading gradiently is 63%; Comprcssive strength is 4.7MPa; PLGA becomes on the membranaceous hole wall attached to the calcium phosphate bone cement porous support, and the chitosan that is filled in internal stent is a cellular, and the aperture is between 20～80 μ m.Though the aperture of chitosan obturator is less than normal, along with chitosan is comparatively fast degraded, support can form the above macropore of 100 μ m, and porosity increases thereupon.After chitosan was degraded fully, the aperture can reach more than the 200 μ m.The composition of material, structure and performance are suitable as bone tissue engineering scaffold and use.And, can in natural polymer, introduce somatomedin as required, give support bone inducing function, promote the growth of new bone.
Embodiment two
1, polylactic acid (PLA) is dissolved in 1, in the 4-dioxane, is mixed with the polylactic acid solution of 5% mass percent concentration, be heated to 40 ℃, stirred 12 hours, treat that polylactic acid fully dissolves, obtain polylactic acid solution, for use.
2, select for use overall porosity to be about 95%, and the bata-tricalcium phosphate of pore size 100～300 μ m (β-TCP)+dicalcium phosphate dehydrate (DCPD) system calcium phosphate bone cement porous support, above-mentioned porous support is put into common electrically heated drying cabinet; Drying is 1 hour under 100 ℃; Take out, be soaked in the polylactic acid solution of step 1 preparation, put into vacuum desiccator; Evacuation 4 hours, polylactic acid solution is filled in the hole of calcium phosphate bone cement porous support under pressure and capillary force action.
3, the timbering material that has poured into PLA in the above-mentioned hole is taken out; Wipe away dried surface with filter paper; Put into-40 ℃ of refrigerator precoolings 6 hours; Lyophilization 36 hours under-40 ℃ of conditions afterwards, promptly getting once-combined calcium orthophosphate base tissue engineering bracket material is the compound multi-porous tissue engineering supporting material of synthetic high polymer and calcium phosphate.
4, with collagenolysis in percent by volume is 1% acetum, be mixed with mass percent concentration and be 10% collagen solution, with magnetic stirrer 2 hours, obtain collagen solution, for use.
5, the once-combined calcium orthophosphate base porous support of step 3 preparation is dipped in the collagen solution that step 4 prepares; Put into vacuum desiccator; Evacuation 2 hours; Collagen solution is filled in the hole of calcium phosphate bone cement porous support under pressure and capillary force action, has obtained pouring into the calcium phosphate bone cement porous support of collagen solution.
The calcium phosphate bone cement porous support that 6, will pass through PLA and collagen MULTIPLE COMPOSITE is that the porous support of step 5 preparation takes out, and wipes away with filter paper and does the surface, puts into-60 ℃ of pre-freezes 1 hour; With the material lyophilization that obtains 24 hours, promptly get multiplex composite bone tissue engineering bracket material capable of degrading gradiently.The final porosity of prepared multiplex composite bone tissue engineering bracket material capable of degrading gradiently is 75%; Comprcssive strength is 2.5MPa; PLA becomes on the membranaceous hole wall attached to the calcium phosphate bone cement porous support; The collagen that is filled in internal stent is mesh structural porous structure, and the aperture is between 50～120 μ m.Though the aperture of collagen obturator is less than normal, along with collagen is degraded fast, support can form the above macropore of 100 μ m, and porosity increases thereupon.After collagen was degraded fully, the aperture can reach 100～300 μ m.The composition of material, structure and performance are suitable as bone tissue engineering scaffold and use.And, can in natural polymer, introduce somatomedin as required, give support bone inducing function, promote the growth of new bone.
Embodiment three
1, will gather own lactone (PCL)/starch blend and be dissolved in the dimethyl sulfoxide, be mixed with the solution of 20% mass percent concentration, be heated to 80 ℃; Left standstill 48 hours; Wait to gather own lactone (PCL)/starch blend and fully dissolve, obtain gathering own lactone (PCL)/starch blend solution, for use.
2, select for use overall porosity to be about 80%, and the bata-tricalcium phosphate of pore size 200～400 μ m (β-TCP)+tetrasodium pyrophosphate (Na
4P
2O
7) system calcium phosphate bone cement porous support; Above-mentioned porous support is put into vacuum drying oven, and 60 ℃ of following vacuum dryings 4 hours take out; Be soaked into gathering in own lactone (PCL)/starch blend solution of step 1 preparation; Put into vacuum desiccator, evacuation 3 hours gathers own lactone (PCL)/starch solution and under pressure and capillary force action, is filled in the hole of calcium phosphate bone cement porous support.
3, having poured into the timbering material that gathers own lactone (PCL)/starch blend in the hole that step 2 is made takes out; Wipe away dried surface with filter paper; Put into-40 ℃ of refrigerator precoolings 2 hours, lyophilization 30 hours under-50 ℃ of conditions afterwards promptly gets once-combined calcium orthophosphate base tissue engineering bracket material.
4, silkworm silk being placed mass percent is 0.05% Na
2CO
3In the solution,, repeat 3 times, slough the sericin in the silkworm silk, obtain refine silkworm silk after the oven dry in 100 ℃ of processing 30min.The refine silk is used CaCl
2-CH
3CH
2OH-H
2O ternary solvent (mol ratio 1: 2: 8) obtains silk fibroin water solution in 70 ℃ of stirring and dissolving after dialysis, filtration, use deionized water preparation mass percent concentration is 5% silk fibroin solution; Use deionized water preparation mass percent concentration is 8% sodium alginate soln.Left standstill 24 hours, and filtered respectively, according to 1: 1 volume ratio two kinds of solution are mixed then, acquisition fibroin albumen, sodium alginate mass content are respectively fibroin albumen/mixed solution of sodium alginate of 2.5% and 4%, and be for use.
5, the once-combined calcium orthophosphate base porous support of step 3 preparation is dipped in fibroin albumen/mixed solution of sodium alginate that step 4 prepares; Put into vacuum desiccator; Evacuation 5 hours; Fibroin albumen/mixed solution of sodium alginate is filled in the hole of calcium phosphate bone cement porous support under pressure and capillary force action, has obtained pouring into the calcium phosphate bone cement porous support of fibroin albumen/mixed solution of sodium alginate.
6, will through the calcium phosphate bone cement porous support that gathering own lactone (PCL)/starch and fibroin albumen/sodium alginate MULTIPLE COMPOSITE and take out, and wipe away with filter paper and do the surface, put into-40 ℃ of pre-freezes 24 hours; With the material lyophilization that obtains 48 hours, promptly get multiplex composite bone tissue engineering bracket material capable of degrading gradiently.The final porosity of prepared multiplex composite bone tissue engineering bracket material capable of degrading gradiently is 60%; Comprcssive strength is 3.7MPa; PCL/ starch becomes on the membranaceous hole wall attached to the calcium phosphate bone cement porous support; Collodion silk fibroin/the sodium alginate that is filled in internal stent is a loose structure, and the aperture is between 30～70 μ m.Though the aperture of collodion silk fibroin/sodium alginate obturator is less than normal, along with the quick degraded of collodion silk fibroin/sodium alginate, support can form the above macropore of 100 μ m, and porosity increases thereupon.After collodion silk fibroin/sodium alginate was degraded fully, the aperture can reach more than the 200 μ m.The composition of material, structure and performance are suitable as bone tissue engineering scaffold and use.And, can in natural polymer, introduce somatomedin as required, give support bone inducing function, promote the growth of new bone.
Embodiment four
1, polylactic acid/polyglycolic acid copolymer (PLGA) is dissolved in the acetone, is mixed with the PLGA solution of 1% mass percent concentration, be heated to 60 ℃, left standstill 36 hours, treat that PLGA fully dissolves, for use.
2, select for use overall porosity to be about 85%, the unformed calcium phosphate (ACP) of pore size 300～400 μ m+calcium phosphate dibasic anhydrous (DCPA) system calcium phosphate bone cement porous support is put into vacuum drying oven with above-mentioned porous support; 50 ℃ of following vacuum dryings 12 hours; Take out, be soaked in the PLGA solution of step 1 preparation, put into Dewar bottle; Evacuation 0.5 hour, PLGA solution is filled in the hole of calcium phosphate bone cement porous support under pressure and capillary force action.
3, the timbering material that has poured into PLGA in the hole is taken out, wipe away with filter paper and do the surface, put into-4 ℃ of refrigerator precoolings 48 hours, lyophilization 36 hours under-60 ℃ of conditions afterwards promptly gets once-combined calcium orthophosphate base tissue engineering bracket material.
4, use distilled water preparation mass percent concentration is 25% sodium alginate soln, leaves standstill 24 hours, filters, and obtains sodium alginate soln, and is for use.
5, the once-combined calcium orthophosphate base porous support of step 3 preparation is dipped in the sodium alginate soln that step 4 prepares; Put into vacuum desiccator; Evacuation 5 hours; Mixed solution of sodium alginate is filled in the hole of calcium phosphate bone cement porous support under pressure and capillary force action, has obtained pouring into the calcium phosphate bone cement porous support of sodium alginate soln.
The calcium phosphate bone cement porous support that 6, will pass through PLGA and sodium alginate MULTIPLE COMPOSITE takes out, and wipes away with filter paper and does the surface, puts into-60 ℃ of pre-freezes 1 hour; With the material that obtains lyophilization 12 hours under-40 ℃ of conditions, promptly get multiplex composite bone tissue engineering bracket material capable of degrading gradiently.The final porosity of prepared multiplex composite bone tissue engineering bracket material capable of degrading gradiently is 65%; Comprcssive strength is 4.0MPa; PLGA becomes on the membranaceous hole wall attached to the calcium phosphate bone cement porous support; The sodium alginate that is filled in internal stent is a loose structure, and the aperture is between 30～60 μ m.Though the aperture of sodium alginate obturator is less than normal, along with the quick degraded of sodium alginate, support can form the above macropore of 100 μ m, and porosity increases thereupon.After sodium alginate was degraded fully, the aperture can reach more than the 300 μ m.The composition of material, structure and performance are suitable as bone tissue engineering scaffold and use.And, can in natural polymer, introduce somatomedin as required, give support bone inducing function, promote the growth of new bone.
Embodiment five
1, polyglycolic acid (PGA) is dissolved in the trichloroacetic acid, is mixed with the polyglycolic acid solution of 20% mass percent concentration, stir and treated that polyglycolic acid fully dissolved in 1 hour, for use.
2, select for use overall porosity to be about 80%, and the type alpha tricalcium phosphate of pore size 100～500 μ m (α-TCP)+dicalcium phosphate dehydrate (DCPD)+calcium carbonate (CaCO
3)+hydroxyapatite (HA)+magnesium phosphate (Mg
3(PO
4)
2)+hydrogen phosphite sodium (NaHSO
3) system bone cement porous support; Above-mentioned porous support is put into vacuum drying oven, and 80 ℃ of following vacuum dryings 3 hours take out; Be soaked in the polyglycolic acid solution of step 1 preparation; Put into vacuum desiccator, evacuation 5 hours, polyglycolic acid solution is filled in the hole of porous support under pressure and capillary force action.
3, the timbering material that has poured into PGA in the hole is taken out, wipe away with filter paper and do the surface, put into-60 ℃ of refrigerator precoolings 1 hour, lyophilization 2 hours under-30 ℃ of conditions afterwards promptly gets once-combined calcium orthophosphate base tissue engineering bracket material.
4, use distilled water preparation mass percent concentration is 10% gelatin solution, stirs 2 hours down at 60 ℃ with constant temperature blender with magnetic force, filters, and obtains gelatin solution, and is for use.
5, once-combined calcium orthophosphate base porous support is dipped in the gelatin solution that step (4) prepared; Put into vacuum desiccator; Evacuation 4 hours; Gelatin solution is filled in the hole of calcium phosphate bone cement porous support under pressure and capillary force action, has obtained pouring into the calcium phosphate bone cement porous support of gelatin solution.
The calcium phosphate bone cement porous support that 6, will pass through PGA and gelatin MULTIPLE COMPOSITE takes out, and wipes away with filter paper and does the surface, puts into-30 ℃ of pre-freezes 20 hours; Lyophilization 30 hours under-50 ℃ of conditions afterwards promptly gets multiplex composite bone tissue engineering bracket material capable of degrading gradiently.The final porosity of prepared multiplex composite bone tissue engineering bracket material capable of degrading gradiently is 55%; Comprcssive strength is 3.3MPa; PGA becomes on the membranaceous hole wall attached to the calcium phosphate bone cement porous support, and the gelatin that is filled in internal stent is a loose structure, and the aperture is between 50～80 μ m.Though the aperture of gelatin obturator is less than normal, along with the very fast degraded of gelatin, support can progressively form the above macropore of 100 μ m, and porosity increases thereupon.After gelatin was degraded fully, the aperture can reach 100～500 μ m.The composition of material, structure and performance are suitable as bone tissue engineering scaffold and use.And, can in natural polymer, introduce somatomedin as required, give support bone inducing function, promote the growth of new bone.
Embodiment six
1, polylactic acid/polyglycolic acid copolymer (PLGA) is dissolved in the chloroform, is made into the solution of 15% mass percent concentration, with magnetic stirrer 6 hours, obtain polylactic acid/polyglycolic acid copolymer solution, it is for use to put into container.
2, select for use overall porosity to be about 75%, the partially crystallized calcium phosphate (PCCP) of pore size 200～500 μ m+calcium phosphate dibasic anhydrous (DCPA) system bone cement porous support is put into vacuum drying oven with porous support; 37 ℃ of following vacuum dryings 36 hours; Take out, be soaked in the PLGA solution of step 1 preparation, put into vacuum desiccator; Evacuation 4 hours, PLGA solution is filled in the hole of porous support under pressure and capillary force action.
3, the timbering material that has poured into PLGA in the hole is taken out, wipe away with filter paper and do the surface, put into-20 ℃ of refrigerator precoolings 12 hours, lyophilization 12 hours under-40 ℃ of conditions afterwards promptly gets once-combined calcium orthophosphate base tissue engineering bracket material.
4, use distilled water preparation mass percent concentration is 6%, 9% cmc soln and sodium alginate soln; Using percent by volume is that 2% dilute acetic acid solution preparation mass percent concentration is 6% chitosan solution.Left standstill 12 hours; Filter respectively; According to 1: 1: 1 volume ratio three kinds of solution are mixed then, obtain carboxymethyl cellulose, sodium alginate and chitosan mass content and be respectively carboxymethyl cellulose/alginate mixed solution of 2%, 3% and 2%, for use.
5, the once-combined calcium orthophosphate base porous support of step 3 preparation is dipped in carboxymethyl cellulose/alginate mixed solution that step 4 prepares; Put into vacuum desiccator; Evacuation 2 hours; Carboxymethyl cellulose/alginate mixed solution is filled in the hole of calcium phosphate bone cement porous support under pressure and capillary force action, has obtained pouring into the calcium phosphate bone cement porous support of carboxymethyl cellulose/alginate mixed solution.
The calcium phosphate bone cement porous support that 6, will pass through PLGA and carboxymethyl cellulose/alginate MULTIPLE COMPOSITE takes out, and wipes away with filter paper and does the surface, puts into-30 ℃ of pre-freezes 20 hours; Lyophilization 48 hours under-40 ℃ of conditions afterwards promptly gets multiplex composite bone tissue engineering bracket material capable of degrading gradiently.The final porosity of prepared multiplex composite bone tissue engineering bracket material capable of degrading gradiently is 52%; Comprcssive strength is 4.2MPa; PLGA becomes on the membranaceous hole wall attached to the calcium phosphate bone cement porous support; Carboxymethyl cellulose/the alginate that is filled in internal stent is a loose structure, and the aperture is between 30～70 μ m.Though the aperture of carboxymethyl cellulose/alginate obturator is less than normal, along with the very fast degraded of carboxymethyl cellulose/alginate, support can progressively form the above macropore of 100 μ m, and porosity increases thereupon.After carboxymethyl cellulose/alginate was degraded fully, the aperture can reach more than the 200 μ m.The composition of material, structure and performance are suitable as bone tissue engineering scaffold and use.And, can in natural polymer, introduce somatomedin as required, give support bone inducing function, promote the growth of new bone.
Embodiment seven
1, polylactic acid (PLA)/starch blend is dissolved in the chloroform, is mixed with the solution of 15% mass percent concentration, stirring is fully dissolved it, and is for use.
2, select for use overall porosity to be about 70%, and the bata-tricalcium phosphate of pore size 200～400 μ m (β-TCP)+tetrasodium pyrophosphate (Na
4P
2O
7) system bone cement porous support; Above-mentioned porous support is put into vacuum drying oven, and 30 ℃ of following vacuum dryings 48 hours take out; Be soaked in the PLA/ starch solution of step 1 preparation; Put into vacuum desiccator, evacuation 4 hours, the PLA/ starch solution is filled in the hole of porous support under pressure and capillary force action.
3, the timbering material that has poured into the PLA/ starch solution in the hole is taken out, wipe away with filter paper and do the surface, put into-30 ℃ of refrigerator precoolings 6 hours, lyophilization 16 hours under-40 ℃ of conditions afterwards promptly gets once-combined calcium orthophosphate base tissue engineering bracket material.
4, the use percent by volume is that 1% dilute acetic acid solution preparation mass percent concentration is 5% collagen solution, mixes 12 hours with magnetic stirrer, obtains collagen solution, and is for use.
5, the once-combined calcium orthophosphate base porous support of step 3 preparation is dipped in the solution that step 4 prepares; Put into vacuum desiccator; Evacuation 2 hours, collagen solution are filled in the hole of calcium phosphate bone cement porous support under pressure and capillary force action; Obtained pouring into the calcium phosphate bone cement porous support of collagen solution.
The calcium phosphate bone cement porous support that 6, will pass through PLA/ starch and collagen MULTIPLE COMPOSITE takes out, and wipes away with filter paper and does the surface, puts into-30 ℃ of pre-freezes 20 hours; Lyophilization 48 hours under-40 ℃ of conditions afterwards promptly gets multiplex composite bone tissue engineering bracket material capable of degrading gradiently.The final porosity of prepared multiplex composite bone tissue engineering bracket material capable of degrading gradiently is 47%; Comprcssive strength is 5.5MPa; PLA/ starch becomes on the membranaceous hole wall attached to the calcium phosphate bone cement porous support; The collagen that is filled in internal stent is mesh structural porous structure, and the aperture is between 50～120 μ m.Though the aperture of collagen obturator is less than normal, along with the quick degraded of collagen, support can progressively form the above macropore of 100 μ m, and porosity increases thereupon.After collagen was degraded fully, the aperture can reach more than the 200 μ m.The composition of material, structure and performance are suitable as bone tissue engineering scaffold and use.And, can in natural polymer, introduce somatomedin as required, give support bone inducing function, promote the growth of new bone.
The above-mentioned specific embodiment is the preferred embodiments of the present invention; Can not limit claim of the present invention; Other any change or other equivalent substitute mode that does not deviate from technical scheme of the present invention and made is included within protection scope of the present invention.
Claims (5)
1. the method for preparing of a multiplex composite bone tissue engineering bracket material capable of degrading gradiently is characterized in that comprising the steps:
(1) the bio-compatible degradable synthesized polymer material is dissolved in the solvent, is mixed with mass percent concentration and is 1～20% solution, stirred then or leave standstill 1～48 hour, filter, obtain synthetic high polymer solution;
Bio-compatible degradable natural macromolecular material is dissolved in the solvent, is mixed with mass percent concentration and is 5～25% solution, stirred then or leave standstill 1～48 hour, filter, obtain natural polymer solution;
(2) with overall porosity be 70～95% calcium phosphate bone cement porous support 30～100 ℃ dry 1～48 hour down; The calcium phosphate bone cement porous support is dipped in the synthetic high polymer solution that step (1) prepared, and vacuum drying 0.5～5 hour has obtained pouring into the calcium phosphate bone cement porous support of synthesized polymer material;
The calcium phosphate bone cement porous support that (3) will pour into synthesized polymer material was wiped away and is done the surface ,-60～-4 ℃ of following pre-freezes 1～48 hour; Freeze the composite lyophilization 2～48 hours with what obtain, promptly get the compound multi-porous tissue engineering supporting material of synthetic high polymer and calcium phosphate;
(4) will be dipped in the natural polymer solution of step (1) by resultant synthetic high polymer of step (3) and the compound multi-porous tissue engineering supporting material of calcium phosphate; Vacuum drying 0.5～5 hour has obtained pouring into the calcium phosphate bone cement porous support of natural polymer solution;
The calcium phosphate bone cement porous support that (5) will pour into natural polymer solution was wiped away and is done the surface ,-60～-4 ℃ of following pre-freezes 1～48 hour; With the frozen material lyophilization that obtains 2～48 hours, promptly get multiplex composite bone tissue engineering bracket material capable of degrading gradiently then;
Described bio-compatible degradable synthesized polymer material comprises in polylactic acid, polyglycolic acid, polylactic acid/polyglycolic acid copolymer, polylactic acid and starch blend, polycaprolactone or the polycaprolactone/starch blend any one or two or more material;
Described bio-compatible degradable natural macromolecular material comprises in collagen, gelatin, chitosan, fibroin albumen, sodium alginate or the cellulose derivative any one or two or more material.
2. the method for preparing of a kind of multiplex composite bone tissue engineering bracket material capable of degrading gradiently according to claim 1; It is characterized in that: the solvent that said bio-compatible degradable synthesized polymer material is dissolved in the solvent is 1,4-dioxane, acetone, dichloromethane, chloroform, dimethyl sulfoxide or trichloroacetic acid.
3. the method for preparing of a kind of multiplex composite bone tissue engineering bracket material capable of degrading gradiently according to claim 1, it is characterized in that: the solvent that said bio-compatible degradable natural macromolecular material is dissolved in the solvent is deionized water, distilled water, aqueous acetic acid, phosphate aqueous solution, dehydrated alcohol, ethanol water, calcium chloride solution or acetone.
4. the method for preparing of a kind of multiplex composite bone tissue engineering bracket material capable of degrading gradiently according to claim 1, it is characterized in that: described calcium phosphate bone cement comprises unformed calcium phosphate+dicalcium phosphate dehydrate system bone cement, tricalcium phosphate+dicalcium phosphate dehydrate system bone cement, type alpha tricalcium phosphate+dicalcium phosphate dehydrate+calcium carbonate+hydroxyapatite system bone cement, type alpha tricalcium phosphate+dicalcium phosphate dehydrate+calcium carbonate+hydroxyapatite+magnesium phosphate+hydrogen phosphite sodium system bone cement, tetracalcium phosphate+calcium phosphate dibasic anhydrous+calcium carbonate system bone cement, bata-tricalcium phosphate+tetrasodium pyrophosphate system bone cement or partially crystallized calcium phosphate+calcium phosphate dibasic anhydrous system bone cement.
5. but a MULTIPLE COMPOSITE gradient degraded calcium phosphate bone tissue engineering rack is prepared from through each said method for preparing of claim 1～4 exactly.
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