CN103830775A - High-strength collagen base artificial bone repair material - Google Patents
High-strength collagen base artificial bone repair material Download PDFInfo
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- CN103830775A CN103830775A CN201210488483.5A CN201210488483A CN103830775A CN 103830775 A CN103830775 A CN 103830775A CN 201210488483 A CN201210488483 A CN 201210488483A CN 103830775 A CN103830775 A CN 103830775A
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Abstract
The invention provides a high-strength collagen base artificial bone repair material which can be used for repairing the bone defect of bearing parts of a human body. The high-strength collagen base artificial bone repair material has chemical composition and structure formed by self-assembly of nanometer calcium phosphate and collagen molecules, so that the high-strength collagen base artificial bone repair material has a biomimetic mineralization structure similar to the natural bone tissue of the human body. In terms of mechanical properties, the material has the mechanical strength similar to that of the cortical bone of the human body and can be used for repairing the bone defect of the bearing parts of the human body. The invention also provides a preparation method of the high-strength collagen base artificial bone repair material.
Description
Technical field
The invention belongs to biomedical materials field, relate to a kind of artificial bone, be specifically related to the high strength collagen-based artificial bone repair materials of a kind of human bearing of can be used for position bone defect repair.
Technical background
The weight bearing area bone causing due to wound, infection, bone tumor etc. is clinically damaged very common, for the damaged reparation of this class, people develop the multiple materials such as titanium alloy, polyether-ether-ketone, carbon fiber, but these materials all exist defect separately aspect mechanical performance and biological activity.The elastic modelling quantity of titanium alloy material is 4～10 times of human bone, has stress shielding phenomenon in clinical practice, is unfavorable for bone reparation.Carbon fibre material easily produces abrasive dust on surface, cause the tissue inflammation reaction of repairing position, affects repairing effect.In addition, the biocompatibility of the materials such as titanium alloy, polyether-ether-ketone, carbon fiber all depends on their biologically inert, they do not have with human body natural bone tissue and form synosteotic biological activity, but use as Permanent implantation body, do not participate in the metabolism of human body, finally be present in body as foreign body, thereby long-term repair effect is undesirable.
Human body natural bone tissue is mainly by forming take collagen as main organic principle with take hydroxyapatite as main inorganic constituents, wherein collagen presents regularly arranged multilevel hierarchy, and for hydroxyapatite provides mineralising template, thereby the mineralized collagen complex of formation ordered arrangement.Imitate composition and the structure of nature bone and manufacture biological activity bone renovating material, by providing the microenvironment similar to nature bone for repairing position, be conducive to attaching, the propagation of osteocyte, promote the damaged reparation of bone.
In recent years, people have developed some hard tissue repair products take collagen/hydroxyapatite as main component, for example guide tissue regeneration (guided tissue regeneration, GTR) film etc.In these products, the mass ratio of collagen and hydroxyapatite is 2/8～7/3, can play the effect that promotes osteanagenesis.But this class GTR film is mainly used in the reparation of non-weight bearing area bone, the such as damaged filling of periodontal bone, the fusion of spinal column transverse process etc., its soft mechanical performance has determined that it can not provide mechanics to support for repairing position.In addition, existing collagen/hydroxyapatite composite bone repairing material mostly is the physical mixed of collagen and hydroxyapatite bi-material, and does not possess the multilevel hierarchy of natural bone tissue.
In order to meet the mechanical performance requirement of bone reparation to material, calcium phosphate bioceramic material take hydroxyapatite as representative has obtained broad research, people have developed the Ca-P ceramic timbering material that possesses certain mechanical strength, for example hydroxyapatite porous bio-ceramic at present.This class material mainly makes biomaterial of calcium and phosphor ceramic by the method for sintering, thereby obtains certain mechanical strength.But requisite sintering process has greatly limited the chemical composition of this series products in calcium phosphate bioceramic preparation process, collagen etc. cannot be compounded in final products the useful organic principle of bone tissue restoration.Sintering Ca-P ceramic is because its fragility is also not suitable for use in weight bearing area bone renovating material.On the other hand, there is bibliographical information, nano-grade hydroxy apatite is more conducive to the Osteoblast Differentiation of cell compared with micron particles, even if that raw material adopts is nano-grade hydroxy apatite (particle diameter < 100nm), sintering later its crystal grain also can be grown up to micron order, thereby greatly reduces the osteogenic activity of material.
Therefore, prior art and product still can not be provided for the bioactive materials that human bearing position bone is repaired, and cannot meet the demand of this class clinical repair.
Summary of the invention
For above-mentioned the deficiencies in the prior art, the invention provides a kind of high strength collagen-based artificial bone repair materials.This material has the chemical composition and structure that nanometer calcium microcosmic salt and tropocollagen molecule self assembly form, thereby possesses the biomimetic mineralization structure similar to human body natural bone tissue.Aspect mechanical property, this material has the mechanical strength approximate with human body cortical bone, can be used for the bone defect repair at human bearing position.The present invention also provides the method for preparing this high strength collagen-based artificial bone repair materials.
A first aspect of the present invention, provides a kind of high strength collagen-based artificial bone repair materials.This material is fine and close homogenizing organic/inorganic composite material, wherein organic facies comprises collagen, can also comprise macromolecule polyester, described macromolecule polyester can be polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polycaprolactone wherein one or more are compound, inorganic phase comprises nanometer calcium microcosmic salt.The organic facies of composite and the mass ratio of inorganic phase are 9/1～4/6.In the time containing macromolecule polyester, in the organic facies of composite, the mass ratio of collagen and macromolecule polyester is 9/1～1/9.
The compressive strength of described high strength collagen-based artificial bone repair materials is 65～150MPa, and bending strength is 20～100MPa.
The particle diameter of described nanometer calcium microcosmic salt is 20～200nm, and the mol ratio of calcium constituent and P elements is 1/1～2/1.Further, described nanometer calcium microcosmic salt is nanometer hydroxyapatite, and particle diameter is 20～200nm.
The molecular weight of described macromolecule polyester is 50,000～200,000.
A second aspect of the present invention, provides the preparation method of high strength collagen-based artificial bone repair materials described in first aspect present invention, comprises following operating procedure:
Step S1, the preparation of nanometer calcium microcosmic salt/collagen bionic composite material powder body, specifically comprise:
Step S1-1, collagen is dissolved in to any in hydrochloric acid, nitric acid or acetic acid, is mixed with the acid solution of collagen, wherein collagen concentration is 5.0 × 10
-5～5.0 × 10
-3g/mL;
Step S1-2, continue whipping step S1-1 gained solution, slowly drip the solution of calcium ions, the addition of calcium ion is that every gram of collagen correspondence adds calcium ion 0.01～0.16mol;
Step S1-3, continue whipping step S1-2 gained solution, slowly drip the solution of phosphorus-containing acid ion, in the addition of phosphate anion and step S1-2, the mol ratio of calcium ion addition is Ca/P=1/1～2/1;
Step S1-4, lasting whipping step S1-3 gained solution, slowly drip NaOH solution to mixed system pH=6～8, and in the time of pH=5～6, mixed system starts to occur precipitating, and in the time of pH=7, white suspension appears in mixed system;
Step S1-5, by step S1-4 gained mixed system leave standstill 24～120 hours, isolate and precipitate and wash away foreign ion, carry out subsequently lyophilization, grind after acquisition composite material powder for subsequent use.
Step S2, the preparation of collagen/nanometer calcium microcosmic salt/macromolecule polyester composite, specifically comprise:
Step S2-1, be 50 by molecular weight, 000～200,000 macromolecule polyester is mixed with the polyphosphazene polymer ester solution that mass body volume concentrations is 0.02～0.15g/mL at 40～70 ℃, wherein said macromolecule polyester can be that wherein one or more are compound for polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polycaprolactone, described solvent is any in Isosorbide-5-Nitrae-dioxane, dichloromethane, chloroform or dimethyl sulfoxide;
Step S2-2, in step S2-1 gained polyphosphazene polymer ester solution, add the composite material powder of step S1-5 gained, and mix homogeneously, make collagen/nanometer calcium microcosmic salt/macromolecule polyester mixing suspension system, wherein in composite material powder and polyphosphazene polymer ester solution, the mass ratio of macromolecule polyester is 1/2～3/2;
To be placed in-20～4 ℃ of environment fully freezing for step S2-3, mixing suspension system that step S2-2 is obtained, can also in liquid nitrogen, carry out cryogenic refrigeration, then lyophilization 24～72 hours, transfer in vacuum drying oven vacuum drying 72～120 hours, make collagen/nanometer calcium microcosmic salt/macromolecule polyester composite;
Step S2-4, the composite that step S2-3 is made are pulverized and sieve, and the composite material powder that filters out particle diameter 100～600 μ m is for subsequent use.
The cold moudling of step S3, composite, specifically comprises:
Step S3-1, take the composite material powder that a certain amount of step S2-4 obtains, pack in cold stamping die;
Step S3-2, exert pressure to mould, and the pressure that makes to be applied on composite material powder reaches 200～1400MPa;
Step S3-3, maintenance pressure 30～300 seconds, obtain high strength collagen-based artificial bone repair materials after the demoulding.
Aforesaid operations step is for the preparation of the high strength collagen-based artificial bone repair materials that contains three kinds of components of collagen/nanometer calcium microcosmic salt/macromolecule polyester.When prepared high strength collagen-based artificial bone repair materials only contains collagen and two kinds of components of nanometer calcium microcosmic salt, and not when pbz polymer polyester, preparation process skips steps S2, step S3-1 becomes: take the composite material powder that a certain amount of step S1-5 obtains, pack in cold stamping die, all the other steps are constant.
A third aspect of the present invention, provides a kind of high strength collagen-based artificial bone repair materials.This material is the double-deck organic/inorganic composite material of densification-porous, wherein organic facies comprises collagen and macromolecule polyester, described macromolecule polyester can be that wherein one or more are compound for polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polycaprolactone, inorganic phase comprises nanometer calcium microcosmic salt, the mass ratio of organic facies and inorganic phase is 9/1～2/8, in organic facies, the mass ratio of collagen and macromolecule polyester is 9/1～1/9.
In described double-decker: lower floor is compacted zone, thickness is 0.5～5mm, and compressive strength is 65～150MPa, and bending strength is 20～100MPa; Upper strata is porous structure layer, and thickness is 0.5～5mm, and porosity is 50%～80%.
The particle diameter of described nanometer calcium microcosmic salt is 20～200nm, and the mol ratio of calcium constituent and P elements is 1/1～2/1.Further, described nanometer calcium microcosmic salt is nanometer hydroxyapatite, and particle diameter is 20～200nm.
The molecular weight of described macromolecule polyester is 50,000～200,000.
A fourth aspect of the present invention, provides the preparation method of densification-porous double-layer high strength collagen-based artificial bone repair materials described in third aspect present invention, comprises following operating procedure:
Step S1, the preparation of nanometer calcium microcosmic salt/collagen bionic composite material powder body, specifically comprise:
Step S1-1, collagen is dissolved in to any in hydrochloric acid, nitric acid or acetic acid, is mixed with the acid solution of collagen, wherein collagen concentration is 5.0 × 10
-5～5.0 × 10
-3g/mL;
Step S1-2, continue whipping step S1-1 gained solution, slowly drip the solution of calcium ions, the addition of calcium ion is that every gram of collagen correspondence adds calcium ion 0.01～0.16mol;
Step S1-3, continue whipping step S1-2 gained solution, slowly drip the solution of phosphorus-containing acid ion, in the addition of phosphate anion and step S1-2, the mol ratio of calcium ion addition is Ca/P=1/1～2/1;
Step S1-4, lasting whipping step S1-3 gained solution, slowly drip NaOH solution to mixed system pH=6～8, and in the time of pH=5～6, mixed system starts to occur precipitating, and in the time of pH=7, white suspension appears in mixed system;
Step S1-5, by step S1-4 gained mixed system leave standstill 24～120 hours, isolate and precipitate and wash away foreign ion, carry out subsequently lyophilization, grind after acquisition composite material powder for subsequent use.
Step S2, the preparation of collagen/nanometer calcium microcosmic salt/macromolecule polyester composite, specifically comprise:
Step S2-1, be 50 by molecular weight, 000～200,000 macromolecule polyester is mixed with the polyphosphazene polymer ester solution that mass body volume concentrations is 0.02～0.15g/mL at 40～70 ℃, wherein said macromolecule polyester can be that wherein one or more are compound for polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polycaprolactone, solvent is any in Isosorbide-5-Nitrae-dioxane, dichloromethane, chloroform or dimethyl sulfoxide;
Step S2-2, in step S2-1 gained polyphosphazene polymer ester solution, add the composite material powder of step S1-5 gained, and mix homogeneously, make collagen/nanometer calcium microcosmic salt/macromolecule polyester mixing suspension system, wherein in composite material powder and polyphosphazene polymer ester solution, the mass ratio of macromolecule polyester is 1/2～3/2;
To be placed in-20～4 ℃ of environment fully freezing for step S2-3, mixing suspension system that step S2-2 is obtained, can also in liquid nitrogen, carry out cryogenic refrigeration, then lyophilization 24～72 hours, transfer in vacuum drying oven vacuum drying 72～120 hours, make collagen/nanometer calcium microcosmic salt/macromolecule polyester composite.
Step S2-4, the composite that step S2-3 is made are pulverized and sieve, and the composite material powder that filters out particle diameter 100～600 μ m is for subsequent use;
The cold moudling of step S3, composite, specifically comprises:
Step S3-1, take the composite material powder that a certain amount of step S2-4 obtains, pack in cold stamping die;
Step S3-2, exert pressure to mould, and the pressure that makes to be applied on composite material powder reaches 200～1400MPa
Step S3-3, maintenance pressure 30～300 seconds, obtain described compacted zone after the demoulding.
Step S4, on compacted zone material, further build porous layer, specifically comprise:
Step S4-1, take step S3-3 obtain compacted zone as substrate, repeating step S1-1～S2-2, in compacted zone substrate, cover collagen/nanometer calcium microcosmic salt/macromolecule polyester mixing suspension that step S2-2 obtains, and leave standstill 2～15min, make surface produce slight dissolving;
Step S4-2, the compacted zone that step S4-1 is obtained and the mixing suspension of upper covering thereof are put into the low temperature environment quick freezing of-20～-10 ℃, then lyophilization 24～72 hours, transfer in vacuum drying oven vacuum drying 72～120 hours, make described densification-porous double-decker high strength collagen-based artificial bone repair materials.
Implement the present invention, can prepare and there is the high strength collagen-based artificial bone suitable with human body cortical bone mechanical performance, can meet the demand that weight bearing area bone is repaired clinically.This material has the main component of the human body natural bone tissue such as collagen and nanometer calcium microcosmic salt, and nanometer calcium microcosmic salt and tropocollagen molecule be self-assembled into nature bone in similarly microstructure, the attaching and the propagation that on composition and structure, are osteocyte provide splendid microenvironment.Generally speaking, high strength collagen-based artificial bone provided by the present invention possesses good biological activity and excellent mechanical performance, and can degrade, fill up at present one of high strength bioactive bone renovating material large blank clinically, have broad application prospects.
Accompanying drawing explanation
Fig. 1 is for according to a second aspect of the invention, the preparation method process chart of high strength collagen-based artificial bone repair materials;
Fig. 2 A and Fig. 2 B be for according to a first aspect of the invention, a kind of high strength collagen-based artificial bone repair materials schematic diagram merging for human spine, and wherein Fig. 2 A is front view, Fig. 2 B is side view;
Fig. 3 is for according to a first aspect of the invention, a kind of high strength collagen-based artificial bone repair materials schematic diagram for human body Laminoplasty;
Fig. 4 is for according to a third aspect of the invention we, densification-porous double-decker high strength collagen-based artificial bone repair materials structural representation;
Fig. 5 is for according to a forth aspect of the invention, the preparation method process chart of densification-porous double-decker high strength collagen-based artificial bone repair materials.
The specific embodiment
For content of the present invention is better described, below in conjunction with the drawings and specific embodiments, the invention will be further described.
Figure 1 shows that the preparation method process chart of high strength collagen-based artificial bone repair materials of the present invention.According to step shown in Fig. 1, the preparation method of high strength collagen/nanometer calcium microcosmic salt cmposite artificial bone is:
Step S1-1,1g collagen is dissolved in to the acetum that 2L concentration is 0.5mol/L, is mixed with the acid solution of collagen;
Step S1-2, lasting whipping step S1-1 gained solution, slowly drip the CaCl that 100mL concentration is 1mol/L
2solution;
Step S1-3, lasting whipping step S1-2 gained solution, slowly drip the Na that 100mL concentration is 0.6mol/L
2hPO
4solution;
Step S1-4, lasting whipping step S1-3 gained solution, slowly drip the NaOH solution of 1mol/L to mixed system pH=7;
Step S1-5, step S1-4 gained mixed system is left standstill to 48 hours, filter out precipitation, and with deionized water centrifuge washing 5 times, carry out subsequently lyophilization, after grinding, acquisition dry powder is for subsequent use.
The cmposite artificial bone of preparing due to the present embodiment does not relate to macromolecule polyester, does not therefore need step S2, and directly enters step S3.
Step S3-1, take the dry powder of 0.6g step S1-5 gained, pack in the mould groove of diameter 12mm;
Step S3-2, to mould pressurizing and reach 75kN;
Step S3-3, maintenance pressure 90 seconds, obtain high strength collagen/nanometer calcium microcosmic salt cmposite artificial bone after the demoulding.
This cmposite artificial bone profile is Φ=12mm, h=3mm disk.After tested, this combined artificial bone density is 1.77g/cm
3, compressive strength is 98MPa, bending strength is 32MPa, is applicable to the reparation of weight bearing area defect of human body bone.
Embodiment 2, the preparation of high strength collagen/nanometer calcium microcosmic salt/polylactic acid cmposite artificial bone
First, according to carrying out the preparation of collagen/nanometer calcium microcosmic salt composite described in embodiment 1 step S1-1～S1-5.
Then, carry out the preparation of collagen/nanometer calcium microcosmic salt/lactic acid composite material, specifically comprise:
Step S2-1, to get molecular weight be that 100,000 polylactic acid 1g is dissolved in 10mL Isosorbide-5-Nitrae-dioxane at 50 ℃, is mixed with polylactic acid solution;
Step S2-2, in step S2-1 gained polylactic acid solution, add the prepared dry powder 1g of step S1-5, and mix homogeneously, make collagen/nanometer calcium microcosmic salt/polylactic acid mixing suspension system;
Step S2-3, by step S2-2 obtain mixing suspension system be placed in-10 ℃ freezing 2 hours, then lyophilization 48 hours, transfer to vacuum and be-vacuum drying oven of 0.1MPa under room temperature dry 72 hours, make collagen/nanometer calcium microcosmic salt/lactic acid composite material;
Step S2-4, the composite that step S2-3 is made are pulverized and sieve, and the composite material powder that filters out particle diameter 100～500 μ m is for subsequent use.
Finally, operate, but in step S3-2, exert pressure as 120kN described in embodiment 1 step S3-1～S3-3, all the other operations and technological parameter are constant, thereby obtain collagen/nanometer calcium microcosmic salt/polylactic acid cmposite artificial bone.
After tested, this combined artificial bone density is 1.85g/cm
3, compressive strength is 129MPa, bending strength is 62MPa, is applicable to the reparation of weight bearing area defect of human body bone.
Embodiment 3, the preparation of high strength collagen/nanometer calcium microcosmic salt/polylactic-co-glycolic acid cmposite artificial bone
Carry out material preparation according to step described in embodiment 2.Wherein, described in step S2-1, to replace with molecular weight be 120 to polylactic acid, 000 polylactic-co-glycolic acid (lactic acid/glycolic=50/50), in step S3-2, exert pressure as 155kN, all the other operations and technological parameter are constant, thereby obtain collagen/nanometer calcium microcosmic salt/polylactic-co-glycolic acid cmposite artificial bone.
After tested, this combined artificial bone density is 1.85g/cm
3, compressive strength is 145MPa, bending strength is 84MPa, is applicable to the reparation of weight bearing area defect of human body bone.
Fig. 2 A and 2B are depicted as a kind of high strength collagen-based artificial bone schematic diagram merging for human spine of the present invention, and wherein Fig. 2 A is front view, and Fig. 2 B is side view.This artificial bone is specially the compound spinal fusion device of a kind of collagen/nanometer calcium microcosmic salt/polycaprolactone.According to step shown in Fig. 1, the preparation method of this spinal fusion device is:
Step S1-1,1g collagen is dissolved in to 1L concentration is 0.1mol/LHCl solution, is mixed with the acid solution of collagen;
Step S1-2, lasting whipping step S1-1 gained solution, slowly drip the CaCl that 150mL concentration is 1mol/L
2solution;
Step S1-3, lasting whipping step S1-2 gained solution, slowly drip the H that 100mL concentration is 1mol/L
3pO
4solution;
Step S1-4, lasting whipping step S1-3 gained solution, slowly drip the NaOH solution of 0.5mol/L to mixed system pH=7;
Step S1-5, step S1-4 gained mixed system is left standstill to 72 hours, filter out precipitation, and by deionized water filtering and washing 5 times, carry out subsequently lyophilization, after grinding, acquisition dry powder is for subsequent use.
Step S2-1, to get molecular weight be that 100,000 polycaprolactone 1g is dissolved in 10mL dichloromethane at 50 ℃, is mixed with polycaprolactone solution;
Step S2-2, in step S2-1 gained polycaprolactone solution, add the prepared dry powder 1g of step S1-5, and mix homogeneously, make collagen/nanometer calcium microcosmic salt/polycaprolactone mixing suspension system;
Step S2-3, the mixing suspension system that step S2-2 is obtained are placed in-10 ℃ and are transferred to liquid nitrogen after freezing 2 hours and carry out cryogenic refrigeration, then lyophilization 48 hours, transfer to vacuum and be-vacuum drying oven of 0.1MPa under room temperature dry 72 hours, make collagen/nanometer calcium microcosmic salt/polycaprolactone composite material;
Step S2-4, the composite that step S2-3 is made are pulverized and sieve, and the composite material powder that filters out particle diameter 100～500 μ m is for subsequent use.
Step S3-1, take the dry powder of 1.66g step S2-4 gained, pack in the mould of suppressing spinal fusion device;
Step S3-2, to mould pressurizing and reach 120kN;
Step S3-3, maintenance pressure 240 seconds, obtain the compound spinal fusion device of high strength collagen/nanometer calcium microcosmic salt/polycaprolactone after the demoulding.
After tested, this spinal fusion device density is 1.8g/cm3, and compressive strength is 106MPa, meets the requirement of spinal fusion material clinically.
Embodiment 5, the preparation of high strength collagen/nanometer calcium microcosmic salt/polyglycolic acid combined artificial vertebral plate
Figure 3 shows that a kind of high strength collagen-based artificial bone schematic diagram for Laminoplasty of the present invention.This artificial bone is specially a kind of collagen/Na Nei meter calcium microcosmic salt/polyglycolic acid combined artificial vertebral plate.According to step shown in Fig. 1, the preparation method of this artificial neural plate is:
Step S1-1,6g collagen is dissolved in to the HNO that 3L concentration is 0.1mol/L
3solution, is mixed with the acid solution of collagen;
Step S1-2, lasting whipping step S1-1 gained solution, slowly dripping 750mL concentration is the Ca (NO of 1mol/L
3)
2solution;
Step S1-3, lasting whipping step S1-2 gained solution, slowly drip (the NH that 750mL concentration is 1mol/L
4)
2hPO
4solution;
Step S1-4, lasting whipping step S1-3 gained solution, slowly drip the NaOH solution of 0.5mol/L to mixed system pH=7;
Step S1-5, step S1-4 gained mixed system is left standstill to 96 hours, filter out precipitation, and by deionized water filtering and washing 5 times, carry out subsequently lyophilization, after grinding, acquisition dry powder is for subsequent use.
Step S2-1, to get molecular weight be that 150,000 polyglycolic acid 9g is dissolved in 200mL chloroform at 65 ℃, is mixed with polyglycolic acid solution;
Step S2-2, in step S2-1 gained polyglycolic acid solution, add the prepared dry powder 6g of step S1-5, and mix homogeneously, make collagen/nanometer calcium microcosmic salt/polyglycolic acid mixing suspension system;
Step S2-3, the mixing suspension system that step S2-2 is obtained are placed in 0 ℃ and are transferred to liquid nitrogen cryogenic refrigeration after freezing 2 hours, then lyophilization 72 hours, transfer to vacuum and be-vacuum drying oven of 0.1MPa under room temperature dry 96 hours, make collagen/nanometer calcium microcosmic salt/polyglycolic acid composite;
Step S2-4, the composite that step S2-3 is made are pulverized and sieve, and the composite material powder that filters out particle diameter 200～500 μ m is for subsequent use.
Step S3-1, take the composite material powder of 11g step S2-4 gained, pack in the mould of suppressing artificial neural plate;
Step S3-2, to mould pressurizing and reach 900kN;
Step S3-3, maintenance pressure 270 seconds, obtain high strength collagen/nanometer calcium microcosmic salt/polyglycolic acid combined artificial vertebral plate after the demoulding.
This artificial neural plate span 45mm, long 30mm, thick 4mm, high 9mm.After tested, this combined artificial bone density is 1.74g/cm
3, compressive strength is 98MPa, bending strength is 36MPa, meets the requirement of Laminoplasty clinically.
Embodiment 6, the preparation of densification-porous double-layer high strength collagen/nanometer calcium microcosmic salt/polylactic acid Composite Bone dummy
Figure 4 shows that densification-porous double-decker high strength collagen-based artificial bone repair materials structural representation of the present invention, wherein lower floor is compacted zone, and thickness is 2mm, and upper strata is porous layer, and thickness is 1mm.Figure 5 shows that the present invention prepares the preparation method process chart of densification-porous double-decker high strength collagen-based artificial bone repair materials.According to step shown in Fig. 5, the preparation method of the repair materials of artificial bone shown in Fig. 4 is:
Step S1-1,0.3g collagen is dissolved in to the acetum that 3L concentration is 0.2mol/L, is mixed with the acid solution of collagen;
Step S1-2, lasting whipping step S1-1 gained solution, slowly drip the CaCl that 100mL concentration is 0.15mol/L
2solution;
Step S1-3, lasting whipping step S1-2 gained solution, slowly drip (the NH that 60mL concentration is 0.15mol/L
4)
2hPO
4solution;
Step S1-4, lasting whipping step S1-3 gained solution, slowly drip the NaOH solution of 0.2mol/L to mixed system pH=7;
Step S1-5, step S1-4 gained mixed system is left standstill to 36 hours, filter out precipitation, and with deionized water centrifuge washing 5 times, carry out subsequently lyophilization, after grinding, acquisition dry powder is for subsequent use.
Step S2-1, to get molecular weight be that 50,000 polylactic acid 0.2g is dissolved in 1.5mL dimethyl sulfoxide at 60 ℃, is mixed with polylactic acid solution;
Step S2-2, in step S2-1 gained polylactic acid solution, add the prepared dry powder 0.25g of step S1-5, and mix homogeneously, make collagen/nanometer calcium microcosmic salt/polylactic acid mixing suspension system;
Step S2-3, by step S2-2 obtain mixing suspension system be placed in 0 ℃ freezing 2 hours, then lyophilization 24 hours, transfer to vacuum and be-vacuum drying oven of 0.1MPa under room temperature dry 72 hours, make collagen/nanometer calcium microcosmic salt/lactic acid composite material;
Step S2-4, the composite that step S2-3 is made are pulverized and sieve, and the composite material powder that filters out particle diameter 100～500 μ m is for subsequent use.
Step S3-1, take the composite material powder of 0.22g step S2-4 gained, pack long 10mm into, in the mould groove of wide 6mm;
Step S3-2, to mould pressurizing and reach 25kN;
Step S3-3, maintenance pressure 240 seconds, obtain required compacted zone after the demoulding.
Step S4-1, the compacted zone that obtains take step S3-3 are as substrate, and repeating step S1-1～S2-2 covers collagen/nanometer calcium microcosmic salt/polylactic acid mixings suspension 70 μ L that step S2-2 obtains in compacted zone substrate, leaves standstill 10min, and now surface produces slight dissolving;
Step S4-2, mix the compacted zone of suspension and put into the low temperature environment quick freezing of-20 ℃ applying described in step S4-1, then lyophilization 36 hours, transfer in vacuum drying oven vacuum drying 96 hours, make densification-porous double-decker high strength collagen-based artificial bone repair materials.
The long 10mm of this densification-porous double-decker high strength collagen-based artificial bone repair materials, wide 6mm, gross thickness 3mm.After tested, the compacted zone density of this double-layer artificial bone is 1.83g/cm
3, porous layer density is 0.35g/cm
3, double-layer artificial bone complex compressive strength is 81MPa, bending strength is 30MPa, is applicable to the comprehensive damaged reparation demand of clinical cortical bone-spongy bone.
Comparative example 1
Prepare polyethylene artificial bone composites according to step described in embodiment 1, wherein, pressure is 15kN described in step S3-2, and all the other technological parameters remain unchanged.
Comparative example 2
Prepare polyethylene artificial bone composites according to step described in embodiment 1, wherein, pressure is 170kN described in step S3-2, and all the other technological parameters remain unchanged.
Comparative example 3
Prepare polyethylene artificial bone composites according to step described in embodiment 1, wherein, the dwell time is 0 second described in step S3-3, and all the other technological parameters remain unchanged.
Comparative example 4
Prepare polyethylene artificial bone composites according to step described in embodiment 2, wherein, pressure is 15kN described in step S3-2, and all the other technological parameters remain unchanged.
Comparative example 5
Prepare polyethylene artificial bone composites according to step described in embodiment 2, wherein, pressure is 170kN described in step S3-2, and all the other technological parameters remain unchanged.
Comparative example 6
Prepare polyethylene artificial bone composites according to step described in embodiment 3, wherein, pressure is 10kN described in step S3-2, and all the other technological parameters remain unchanged.
Comparative example 7
Prepare polyethylene artificial bone composites according to step described in embodiment 3, wherein, pressure is 170kN described in step S3-2, and all the other technological parameters remain unchanged.
Comparative example 8
Prepare polyethylene artificial bone composites according to step described in embodiment 3, wherein, pressure is 120kN described in step S3-2, and the dwell time is 10s described in step S3-3, and all the other technological parameters remain unchanged.
Comparative example 9
Prepare compound spinal fusion device according to step described in embodiment 4, wherein, pressure is 25kN described in step S3-2, and all the other technological parameters remain unchanged.
Comparative example 10
Prepare compound spinal fusion device according to step described in embodiment 4, wherein, pressure is 225kN described in step S3-2, and all the other technological parameters remain unchanged.
Comparative example 11
Prepare compound spinal fusion device according to step described in embodiment 4, wherein, the dwell time is 20 seconds described in step S3-3, and all the other technological parameters remain unchanged.
Comparative example 12
Prepare combined artificial vertebral plate according to step described in embodiment 5, wherein, pressure is 100kN described in step S3-2, and all the other technological parameters remain unchanged.
Comparative example 13
Prepare combined artificial vertebral plate according to step described in embodiment 5, wherein, pressure is 200kN described in step S3-2, and all the other technological parameters remain unchanged.
The material that above-mentioned comparative example is obtained carries out Mechanics Performance Testing, test result as shown in the following chart:
| Comparative example | The pressure of colding pressing | Dwell time | Sample mechanical performance |
| Comparative example 1 | 133MPa | 90s | Compressive strength 32MPa, bending strength 21MPa |
| Comparative example 2 | 1503MPa | 90s | When sample layering, the demoulding, split |
| Comparative example 3 | 663MPa | 0s | After the sample demoulding, crack |
| Comparative example 4 | 133MPa | 90s | Compressive strength 35MPa, bending strength 22MPa |
| Comparative example 5 | 1503MPa | 90s | When sample layering, the demoulding, split |
| Comparative example 6 | 88MPa | 90s | Material is molding not, when the demoulding, scatters |
| Comparative example 7 | 1503MPa | 90s | Sample demoulding layered, split |
| Comparative example 8 | 1061MPa | 10s | After the sample demoulding, crack |
| Comparative example 9 | 162MPa | 240s | Compressive strength 46MPa, bending strength 23MPa |
| Comparative example 10 | 1461MPa | 240s | When sample layering, the demoulding, split |
| Comparative example 11 | 779MPa | 20s | After the sample demoulding, crack |
| Comparative example 12 | 74MPa | 270s | Material is molding not, when the demoulding, scatters |
| Comparative example 13 | 148MPa | 270s | Compressive strength 34MPa, bending strength 20MPa |
According to above-mentioned comparative example, can find out:
When applied pressure in step S3-2 too hour, sample cannot molding (comparative example 6,11) or poor mechanical properties, cannot meet human bearing position bone reparation requirement (comparative example 1,4,8,12);
In the time that in step S3-2, applied pressure is too large, sample produces layering in pressing process, when the demoulding, split (comparative example 2,5,9);
In the time of too short (comparative example 8,11) even not pressurize of dwell time in step S3-3 (comparative example 3), even applied pressure meets forming materials condition in step S3-2, but due to reasons such as internal residual stress, sample is cracked very soon after the demoulding, thereby cause product to be prepared unsuccessfully.
Comparative example 14
Prepare two-layer compound bone repair according to step described in embodiment 4, wherein, in step S4-1, in compacted zone substrate, cover after collagen/nanometer calcium microcosmic salt/polylactic acid mixings suspension that step S2-2 obtains standing, and the freezing and lyophilization that directly enters step S4-2, all the other technological parameters remain unchanged.
After testing, in prepared 10 samples of the technique of above-mentioned comparative example 14,6 after lyophilization compacted zone and porous layer come off, all the other samples taking, move, all occur in testing process the phenomenon that compacted zone and porous layer come off.This is in the step S4-1 due to above-described embodiment 4, and standing process can make the upper surface of compacted zone substrate produce slight dissolving, makes to have produced a transition zone between compacted zone and porous layer, makes can combine between compacted zone and porous layer.Therefore,, in preparation densification-porous two-layer compound bone repair process, leave standstill process described in step S4-1 and be absolutely necessary.
The present invention is described according to specific embodiment, but it will be understood by those skilled in the art that in the time not departing from the scope of the invention, can carry out various variations and be equal to replacement.In addition,, for adapting to specific occasion or the material of the technology of the present invention, can carry out many modifications and not depart from its protection domain the present invention.Therefore, the present invention is not limited to specific embodiment disclosed herein, and comprises all embodiment that drop into claim protection domain.
Claims (15)
1. a high strength collagen-based artificial bone repair materials, is characterized in that, this material is fine and close homogenizing organic/inorganic composite material, wherein,
Organic facies comprises collagen,
Inorganic phase comprises nanometer calcium microcosmic salt,
The mass ratio of organic facies and inorganic phase is 9/1～4/6.
2. a kind of high strength collagen-based artificial bone repair materials according to claim 1, it is characterized in that, the organic facies of this material also comprises macromolecule polyester, described macromolecule polyester is that wherein one or more are compound for polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polycaprolactone, the mass ratio of organic facies and inorganic phase is 9/1～4/6, in organic facies, the mass ratio of collagen and macromolecule polyester is 9/1～1/9.
3. a kind of high strength collagen-based artificial bone repair materials according to claim 1 and 2, is characterized in that, the compressive strength of this material is 65～150MPa, and bending strength is 20～100MPa.
4. a kind of high strength collagen-based artificial bone repair materials according to claim 1 and 2, is characterized in that, the particle diameter of described nanometer calcium microcosmic salt is 20～200nm, and the mol ratio of calcium constituent and P elements is 1/1～2/1.
5. according to a kind of high strength collagen-based artificial bone repair materials described in claim or 1 or 2, it is characterized in that, described nanometer calcium microcosmic salt is nanometer hydroxyapatite, and particle diameter is 20～200nm.
6. a kind of high strength collagen-based artificial bone repair materials according to claim 2, is characterized in that, the molecular weight of described macromolecule polyester is 50,000～200,000.
7. a method of preparing high strength collagen-based artificial bone repair materials described in claim 1, is characterized in that comprising the following steps:
Step S1, the preparation of nanometer calcium microcosmic salt/collagen bionic composite material powder body, specifically comprise:
Step S1-1, collagen is dissolved in to any in hydrochloric acid, nitric acid or acetic acid, is mixed with the acid solution of collagen, wherein collagen concentration is 5.0 × 10
-5～5.0 × 10
-3g/mL;
Step S1-2, continue whipping step S1-1 gained solution, slowly drip the solution of calcium ions, the addition of calcium ion is that every gram of collagen correspondence adds calcium ion 0.01～0.16mol;
Step S1-3, continue whipping step S1-2 gained solution, slowly drip the solution of phosphorus-containing acid ion, in the addition of phosphate anion and step S1-2, the mol ratio of calcium ion addition is Ca/P=1/1～2/1;
Step S1-4, lasting whipping step S1-3 gained solution, slowly drip NaOH solution to mixed system pH=6～8, and in the time of pH=5～6, mixed system starts to occur precipitating, and in the time of pH=7, white suspension appears in mixed system;
Step S1-5, by step S1-4 gained mixed system leave standstill 24～120 hours, isolate and precipitate and wash away foreign ion, carry out subsequently lyophilization, grind after acquisition composite material powder for subsequent use;
The cold moudling of step S2, composite, specifically comprises:
Step S2-1, take the composite material powder of a certain amount of step S1-5 gained, pack in cold stamping die;
Step S2-2, exert pressure to mould, and the pressure that makes to be applied on composite material powder reaches 200～1400MPa;
Step S2-3, maintenance pressure 30～300 seconds, obtain high strength collagen-based artificial bone repair materials after the demoulding.
8. a method of preparing high strength collagen-based artificial bone repair materials described in claim 2, is characterized in that comprising the following steps:
Step S1, the preparation of nanometer calcium microcosmic salt/collagen bionic composite material powder body, specifically comprise:
Step S1-1, collagen is dissolved in to any in hydrochloric acid, nitric acid or acetic acid, is mixed with the acid solution of collagen, wherein collagen concentration is 5.0 × 10
-5～5.0 × 10
-3g/mL;
Step S1-2, continue whipping step S1-1 gained solution, slowly drip the solution of calcium ions, the addition of calcium ion is that every gram of collagen correspondence adds calcium ion 0.01～0.16mol;
Step S1-3, continue whipping step S1-2 gained solution, slowly drip the solution of phosphorus-containing acid ion, in the addition of phosphate anion and step S1-2, the mol ratio of calcium ion addition is Ca/P=1/1～2/1;
Step S1-4, lasting whipping step S1-3 gained solution, slowly drip NaOH solution to mixed system pH=6～8, and in the time of pH=5～6, mixed system starts to occur precipitating, and in the time of pH=7, white suspension appears in mixed system;
Step S1-5, by step S1-4 gained mixed system leave standstill 24～120 hours, isolate and precipitate and wash away foreign ion, carry out subsequently lyophilization, grind after acquisition composite material powder for subsequent use;
Step S2, the preparation of collagen/nanometer calcium microcosmic salt/macromolecule polyester composite, specifically comprise:
Step S2-1, be 50 by molecular weight, 000～200,000 macromolecule polyester is mixed with the polyphosphazene polymer ester solution that mass body volume concentrations is 0.02～0.15g/mL at 40～70 ℃, wherein said macromolecule polyester is that wherein one or more are compound for polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polycaprolactone, solvent is any in Isosorbide-5-Nitrae-dioxane, dichloromethane, chloroform or dimethyl sulfoxide;
Step S2-2, in step S2-1 gained polyphosphazene polymer ester solution, add the composite material powder of step S1-5 gained, and mix homogeneously, make collagen/nanometer calcium microcosmic salt/macromolecule polyester mixing suspension system, wherein in composite material powder and polyphosphazene polymer ester solution, the mass ratio of macromolecule polyester is 1/2～3/2;
To be placed in-20～4 ℃ of environment fully freezing for step S2-3, mixing suspension system that step S2-2 is obtained, then lyophilization 24～72 hours, transfer in vacuum drying oven vacuum drying 72～120 hours, make collagen/nanometer calcium microcosmic salt/macromolecule polyester composite;
Step S2-4, the composite that step S2-3 is made are pulverized and sieve, and the composite material powder that filters out particle diameter 100～600 μ m is for subsequent use;
The cold moudling of step S3, composite, specifically comprises:
Step S3-1, take the composite material powder that a certain amount of step S2-4 obtains, pack in cold stamping die;
Step S3-2, exert pressure to mould, and the pressure that makes to be applied on composite material powder reaches 200～1400MPa;
Step S3-3, maintenance pressure 30～300 seconds, obtain high strength collagen-based artificial bone repair materials after the demoulding.
9. the method for a kind of high strength collagen-based artificial bone repair materials according to claim 8, it is characterized in that, the mixing suspension system that step S2-2 is obtained of step S2-3 be placed in-20～4 ℃ of environment fully freezing after, also be included in and in liquid nitrogen, carry out cryogenic refrigeration, then lyophilization 24～72 hours, transfer in vacuum drying oven vacuum drying 72～120 hours, make collagen/nanometer calcium microcosmic salt/macromolecule polyester composite.
10. a high strength collagen-based artificial bone repair materials, is characterized in that, this material is the double-deck organic/inorganic composite material of densification-porous, wherein:
Described organic facies comprises collagen and macromolecule polyester; Described macromolecule polyester is that wherein one or more are compound for polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polycaprolactone; Described inorganic phase comprises nanometer calcium microcosmic salt; The mass ratio of organic facies and inorganic phase is 9/1～2/8; In organic facies, the mass ratio of collagen and macromolecule polyester is 9/1～1/9;
In described double-decker, lower floor is compacted zone, and thickness is 0.5～5mm, and compressive strength is 65～150MPa, and bending strength is 20～100MPa; Upper strata is porous structure layer, and thickness is 0.5～5mm, and porosity is 50%～80%.
11. a kind of high strength collagen-based artificial bone repair materials according to claim 10, is characterized in that, the particle diameter of described nanometer calcium microcosmic salt is 20～200nm, and the mol ratio of calcium constituent and P elements is 1/1～2/1.
12. a kind of high strength collagen-based artificial bone repair materials according to claim 10, is characterized in that, described nanometer calcium microcosmic salt is nanometer hydroxyapatite, and particle diameter is 20～200nm.
13. a kind of high strength collagen-based artificial bone repair materials according to claim 10, is characterized in that, the molecular weight of described macromolecule polyester is 50,000～200,000.
Prepare in claim 10-13 the method for high strength collagen-based artificial bone repair materials described in any one, it is characterized in that comprising the following steps for 14. 1 kinds:
Step S1, the preparation of nanometer calcium microcosmic salt/collagen bionic composite material powder body, specifically comprise:
Step S1-1, collagen is dissolved in to any in hydrochloric acid, nitric acid or acetic acid, is mixed with the acid solution of collagen, wherein collagen concentration is 5.0 × 10
-5～5.0 × 10
-3g/mL;
Step S1-2, continue whipping step S1-1 gained solution, slowly drip the solution of calcium ions, the addition of calcium ion is that every gram of collagen correspondence adds calcium ion 0.01～0.16mol;
Step S1-3, continue whipping step S1-2 gained solution, slowly drip the solution of phosphorus-containing acid ion, in the addition of phosphate anion and step S1-2, the mol ratio of calcium ion addition is Ca/P=1/1～2/1;
Step S1-4, lasting whipping step S1-3 gained solution, slowly drip NaOH solution to mixed system pH=6～8, and in the time of pH=5～6, mixed system starts to occur precipitating, and in the time of pH=7, white suspension appears in mixed system;
Step S1-5, by step S1-4 gained mixed system leave standstill 24～120 hours, isolate and precipitate and wash away foreign ion, carry out subsequently lyophilization, grind after acquisition composite material powder for subsequent use;
Step S2, the preparation of collagen/nanometer calcium microcosmic salt/macromolecule polyester composite, specifically comprise:
Step S2-1, be 50 by molecular weight, 000～200,000 macromolecule polyester is mixed with the polyphosphazene polymer ester solution that mass body volume concentrations is 0.02～0.15g/mL at 40～70 ℃, wherein said macromolecule polyester is that wherein one or more are compound for polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polycaprolactone, solvent is any in Isosorbide-5-Nitrae-dioxane, dichloromethane, chloroform or dimethyl sulfoxide;
Step S2-2, in step S2-1 gained polyphosphazene polymer ester solution, add the composite material powder of step S1-5 gained, and mix homogeneously, make collagen/nanometer calcium microcosmic salt/macromolecule polyester mixing suspension system, wherein in composite material powder and polyphosphazene polymer ester solution, the mass ratio of macromolecule polyester is 1/2～3/2;
To be placed in-20～4 ℃ of environment fully freezing for step S2-3, mixing suspension system that step S2-2 is obtained, then lyophilization 24～72 hours, transfer in vacuum drying oven vacuum drying 72～120 hours, make collagen/nanometer calcium microcosmic salt/macromolecule polyester composite;
Step S2-4, the composite that step S2-3 is made are pulverized and sieve, and the composite material powder that filters out particle diameter 100～600 μ m is for subsequent use;
The cold moudling of step S3, composite, specifically comprises:
Step S3-1, take the composite material powder that a certain amount of step S2-4 obtains, pack in cold stamping die;
Step S3-2, exert pressure to mould, and the pressure that makes to be applied on composite material powder reaches 200～1000MPa;
Step S3-3, maintenance pressure 30～300 seconds, obtain described compacted zone after the demoulding;
Step S4, on compacted zone material, further build porous layer, specifically comprise:
Step S4-1, take step S3-3 obtain compacted zone as substrate, repeating step S1-1～S2-2, in compacted zone substrate, cover collagen/nanometer calcium microcosmic salt/macromolecule polyester mixing suspension that step S2-2 obtains, and leave standstill 2～15min, make surface produce slight dissolving;
Step S4-2, the compacted zone that step S4-1 is obtained and the mixing suspension of upper covering thereof are put into the low temperature environment quick freezing of-20～-10 ℃, then lyophilization 24～72 hours, transfer in vacuum drying oven vacuum drying 72～120 hours, make densification-porous double-decker high strength collagen-based artificial bone repair materials.
The method of 15. a kind of high strength collagen-based artificial bone repair materials according to claim 14, it is characterized in that, the mixing suspension system that step S2-2 is obtained of step S2-3 be placed in-20～4 ℃ of environment fully freezing after, also be included in and in liquid nitrogen, carry out cryogenic refrigeration, then lyophilization 24～72 hours, transfer in vacuum drying oven vacuum drying 72～120 hours, make collagen/nanometer calcium microcosmic salt/macromolecule polyester composite.
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| CN113694254A (en) * | 2021-09-06 | 2021-11-26 | 北京博辉瑞进生物科技有限公司 | Bone repair material, preparation method and application thereof |
| CN115137883A (en) * | 2022-08-03 | 2022-10-04 | 尧舜泽生物医药(南京)有限公司 | Bionic composite mineralized scaffold and preparation method thereof |
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