CN102784014B - Porotic bone scaffold and preparation method thereof - Google Patents
Porotic bone scaffold and preparation method thereof Download PDFInfo
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- CN102784014B CN102784014B CN201210288452.5A CN201210288452A CN102784014B CN 102784014 B CN102784014 B CN 102784014B CN 201210288452 A CN201210288452 A CN 201210288452A CN 102784014 B CN102784014 B CN 102784014B
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Abstract
The invention provides a porotic bone scaffold, which is formed by biological activity additives, degradable metal, degradable inorganic substances and degradable polymers. The porotic bone scaffold is in a shape of a cuboid, a cylinder, a cube or a cylinder with a cross section being diamond-shaped; a plurality of holes is formed in the porotic bone scaffold; the connection rate of the holes is greater than 97 percent; a plurality of micropores is formed in hole walls of the holes; a pore diameter of each hole is 100-800 mum; a pore diameter of each micropore is 5-100 mum, and a hole depth of each micropore is 1-50 mum; and the porosity of the porotic bone scaffold is 60-95 percent. Due to a porotic structure, the adhesion of bone tissue cells and the transmission of nutrients are favored, the cells can be effectively fixed so as to be differentiated and proliferated, a favorable growing environment is provided for cell growth, and the repair of defected bone tissue is favored to be realized. The invention also provides a preparation method of the porotic bone scaffold.
Description
Technical field
The present invention relates to biomedical tissue field of engineering technology, particularly relate to a kind of porous bone support and preparation method thereof.
Background technology
Along with social development, the damaged particularly Long bone defect of bone that aged tendency of population, wound, bone tumor etc. cause becomes the thorny problem on Orthopedic Clinical.Rise year by year owing to lacking the number that appropriate therapeutic method disables, bring and have a strong impact on for social stability and people's living standard.The traditional Biotherapy method of bone defect healing comprises fibula and ilium and other bone implantation methods etc. of self bone transplanting, homologous cancellus, application blood vessel transplantation, exists donor deficiency, rejection, graft donor site complication, operation to expend the defects such as large period is long.Bone tissue engineer is that human body cell is planted to the timbering material with biocompatibility, after cell breeds, breaks up to a certain extent on support, again implantable bone defect, along with the continuation proliferation and differentiation of cell and the degraded of timbering material, form new have with institute defective bone organize homologue's organ, bone tissue engineer technology has overcome the shortcoming of traditional bone Defect technology, is the focus of the damaged treatment technology research of osseous tissue.Preparation has biocompatibility, biodegradability, has height intercommunicating pore structure, the porous porous bone support of controlled hole dimension and the geometric shape identical with repaired osseous tissue is one of key technology of bone tissue engineer, so that cell and nutrient transmit smoothly in support, provide space and the region of cell attachment, growth and propagation.
Utilizing multiple material compound is the hot research direction of current bone tissue engineering scaffold, by the compound demand that can meet the needed safety of bone tissue engineering scaffold, degradability, mechanical property of multiple material.In addition, the structural design of porous bone support also plays on the bone repair ability of bone tissue engineering scaffold the impact can not be ignored.The duct of the porous bone support of porous is the nutrient substance conveyance conduit of Growth of Cells, and the size in its aperture plays vital impact to bone growth, the excessive adhesion that is unfavorable for cell in aperture, too small growth, propagation and the differentiation that is unfavorable for cell.And micropore on hole wall has increased the roughness of hole wall, can promote cell adhesion.Cell adhesion is the basis of tissue growth, first effectively fixed cell of porous bone support, and then make its Differentiation and proliferation.Meanwhile, the micropore of connection also can play the effect of nutrient transmission and metabolism.Therefore, if there is the macropore connecting, aperture is suitable in the porous bone support of preparing, in keeping good porosity, the suitable a large amount of micropores of aperture and hole depth can distribute again on hole wall, can be for the growth of bone and its cells provides a most favourable environment, form the new reparation of organizing homologue's organ with defective bone and realize defective bone tissue that has.
But the processing method of bone engineering rack mainly contains particle deposition method, gases at high pressure foaming, electrostatic spinning technique, porogen method etc. at present at present.Said method all exists different defects and restrictive condition.As particle deposition method exists the shortcomings such as hole communicating passage is irregular, too small, uncontrollable, be unfavorable for cell migration; Porogen method exists the residual formation cytotoxicity of porogen; Too small or the hole of support hole prepared by gases at high pressure foaming is not communicated with and is unfavorable for cell adhesion and growth; Support mechanical property prepared by electrostatic spinning technique is lower etc., and the controllability of said method is lower, makes the porous bone support preparing be difficult to meet the requirement to pore size, porosity, hole wall specific surface area.
Summary of the invention
Based on this, be necessary to provide a kind of porous bone support of favourable growing environment and preparation method thereof can be provided for bone and its cells.
A kind of porous bone support, described porous bone support is by biological activity additive, degradable metal, degradable inorganic matter and degradable polymer form, described porous bone support be shaped as cuboid, cylinder, square or cross section are the cylinder of rhombus, on described porous bone support, form multiple holes, the connection rate of hole is greater than 97%, on the hole wall of described hole, be formed with multiple micropores, the aperture of described hole is 100 ~ 800 microns, the aperture of described micropore is 5 ~ 100 microns, 1 ~ 50 micron of hole depth, the porosity of described porous bone support is 60 ~ 95%.
In an embodiment, described porosity is 80 ~ 90% therein, and the aperture of described hole is 300 ~ 500 microns, and the aperture of described micropore is 20 ~ 30 microns of 5 ~ 20 microns, hole depth.
A preparation method for porous bone support, comprises the steps:
Biological activity additive is dissolved in the first solvent, obtains the first solution;
Degradable metal, degradable inorganic matter and degradable polymer are dissolved in the second solvent, obtain the second solution;
Mix described the first solution and the second solution, obtain mixed liquor;
With the damaged skeleton cross-section image of MEDCAD module statistical analysis in modular construction software Mimics, and measure the size of described damaged skeleton, create cad model according to described analysis and measurement result, derive the data that contain described cad model;
By delamination software, the described data that contain cad model are carried out to layering processing and obtain the data after layering, lift height is 0.05 ~ 0.2 millimeter, and nozzle angle is 0 ~ 179 ° of conversion;
Described mixed liquor is added in low temperature rapid shaping instrument, and by the data importing low temperature rapid shaping instrument after described layering, at-40 ~-10 DEG C of temperature, carry out 3 D-printing according to the data after described layering and form cuboid, cylinder, square or cross section are the cylinder porous bone support blank of rhombus, the spray webbing spacing of described 3 D-printing is 0.5 ~ 2 millimeter, spray head speed is 4 ~ 30 mm/second, the liquid rate of outflow is 0.1 ~ 1 ml/min, in described porous bone support blank, be formed with multiple apertures and be the hole of 100 ~ 800 microns, the connection rate of hole is greater than 97%,
Described porous bone support blank is processed after 5 minutes ~ 1 hour at-196 ~-40 DEG C of temperature, carry out vacuum drying and obtain porous bone support, on the hole wall of the hole of described porous bone support, be formed with multiple micropores, the aperture of described micropore is that 5 ~ 100 microns, hole depth are 1 ~ 50 micron, and the porosity of described porous bone support is 60 ~ 95%.
In an embodiment, the mass ratio of degradable metal, degradable inorganic matter and degradable polymer is 1:1 ~ 3:1 ~ 5 therein, and in described mixed liquor, the mass ratio of the active additive of described thing and degradable polymer is 1:100 ~ 10000.
In an embodiment, described biological activity additive is selected from least one in chitosan, collagen, bone morphogenetic protein(BMP), icariin, Herba Epimedii therein.
Therein in an embodiment, described degradable metal is selected from the alloy of at least two kinds of formation in a kind of or magnesium in magnesium, ferrum, aluminum, zinc, strontium and manganese, ferrum, aluminum, zinc, strontium, manganese.
In an embodiment, described degradable inorganic matter is selected from least one in tricalcium phosphate, hydroxyapatite, calcium phosphate, calcium silicates, magnesium oxide, magnesium hydroxide, magnesium chloride, magnesium carbonate, magnesium phosphate, magnesium silicate, ferrum oxide, titanium dioxide three-iron, hydrated ferric oxide., iron chloride and strontium carbonate therein.
Therein in an embodiment, described degradable polymer is Porous poly-lactide-co-glycolide, polylactic acid, polyglycolic acid, polycaprolactone, poe, poly-anhydride, polyphosphazene or polyamino acid, or is the copolymer of at least two kinds of formation in Porous poly-lactide-co-glycolide, polylactic acid, polyglycolic acid, polycaprolactone, poe, poly-anhydride, polyphosphazene, polyamino acid.
In an embodiment, described degradable metal is that particle diameter is that 100 ~ 500 object metal dusts or diameter are the thread metal of 1 ~ 500 micron therein.
In an embodiment, described degradable inorganic matter is that particle diameter is the Powdered inorganic matter of 100 ~ 500 object therein.
In an embodiment, described the first solvent and the second solvent are selected from the one in Isosorbide-5-Nitrae-dioxane, acetonitrile, cyclohexane extraction, acetone, ethylene glycol, Ketohexamethylene and dichloromethane therein.
Therein in an embodiment, described vacuum drying step is below vacuum 20Pa, at 10 ~ 30 DEG C of temperature dry 12 ~ 48 hours.
Above-mentioned porous bone support is by biological activity additive, degradable metal, what degradable inorganic matter and degradable polymer formed is shaped as cuboid, cylinder, square or cross section are the porous bone support of the cylinder of rhombus, biological activity additive, degradable metal, the complex of degradable inorganic matter and degradable polymer can provide the inductivity of bone and its cells differentiation, on porous bone support, be formed with aperture and be the hole of 100 ~ 800 microns, the connection rate of hole is greater than 97%, on the hole wall of hole, be formed with aperture and be the micropore of 5 ~ 100 microns, hole depth is 1 ~ 50 micron, the porosity of porous bone support is 60 ~ 95, this porous structure is conducive to the adhesion of bone and its cells and the transmission of nutrient, enough effective fixed cells, and then make its Differentiation and proliferation, for Growth of Cells provides a favourable growing environment, be conducive to realize the reparation of defective bone tissue.
Brief description of the drawings
Fig. 1 is the structural representation of the porous bone support of an embodiment;
Fig. 2 is the preparation method flow chart of the porous bone support of an embodiment;
Fig. 3 is the elementary analysis figure of the porous bone support prepared of embodiment 1;
Fig. 4 is the cross section scanning electron microscope (SEM) photograph (50X) of the porous bone support prepared of embodiment 1;
Fig. 5 is the scanning electron microscope (SEM) photograph (80X) of the longitudinal section of the porous bone support prepared of embodiment 1;
Fig. 6 is the scanning electron microscope (SEM) photograph (500X) of the longitudinal section of the porous bone support prepared of embodiment 1;
Fig. 7 is the scanning electron microscope (SEM) photograph (1000X) of the porous bone support prepared of embodiment 1;
Fig. 8 is the scanning electron microscope (SEM) photograph (5000X) of the porous bone support prepared of embodiment 1;
Fig. 9 is the scanning electron microscope (SEM) photograph of normal spongy bone.
Detailed description of the invention
By detailed description of the invention and accompanying drawing, above-mentioned porous bone support and preparation method thereof is further set forth below.
Refer to Fig. 1, the porous bone support of an embodiment, this porous bone support is formed by biological activity additive, degradable metal, degradable inorganic matter and degradable polymer, this porous bone support be shaped as cuboid.On porous bone support, be formed with multiple holes, hole connection rate is greater than 97%.The aperture of hole is 100 ~ 800 microns.
The hole wall of hole is formed with multiple micropores, and the aperture of micropore is 5 ~ 100 microns, 1 ~ 50 micron of hole depth.The porosity of porous bone support is 60 ~ 95%.
Preferably, the porosity of porous bone support is 80 ~ 90%, and the aperture of hole is 300 ~ 500 microns, 20 ~ 30 microns of hole depths.With this understanding, the surface roughness of cell adhesion can either be provided, and for the transmission of nutrient provides suitable passage, certain mechanical property requirements can be met again.
Biological activity additive is selected from least one in chitosan, collagen, bone morphogenetic protein(BMP), icariin, Herba Epimedii.
Degradable metal is selected from the alloy of at least two kinds of formation in one in magnesium (Mg), ferrum (Fe), aluminum (Al), zinc (Zn), strontium (Sr) and manganese (Mn) or magnesium (Mg), ferrum (Fe), aluminum (Al), zinc (Zn), strontium (Sr), manganese (Mn).The metal or alloy that preferably purity is greater than 99%.
Degradable inorganic matter is selected from least one in tricalcium phosphate (TCP), hydroxyapatite (HA), calcium phosphate, calcium silicates, magnesium oxide, magnesium hydroxide, magnesium chloride, magnesium carbonate, magnesium phosphate, magnesium silicate, ferrum oxide, titanium dioxide three-iron, hydrated ferric oxide., iron chloride and strontium carbonate.
Degradable polymer is Porous poly-lactide-co-glycolide (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), poe, poly-anhydride, polyphosphazene or polyamino acid, or is the copolymer of at least two kinds of formation in Porous poly-lactide-co-glycolide (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), poe, poly-anhydride, polyphosphazene or polyamino acid.
The mass ratio of degradable metal, degradable inorganic matter and degradable polymer is 1: 1 ~ 3:1 ~ 5, and the mass ratio of biological activity additive and degradable polymer is 1:100 ~ 10000.
Be appreciated that in other are implemented.Porous bone support can be also cylindrical, square or the cross section cylinder porous bone support that is rhombus.
Above-mentioned porous bone support is by biological activity additive, degradable metal, what degradable inorganic matter and degradable polymer formed is shaped as cuboid, cylinder or cross section are the porous bone support of the cylinder of rhombus, biological activity additive, degradable metal, the complex of degradable inorganic matter and degradable polymer can provide the inductivity of bone and its cells differentiation, on porous bone support, be formed with aperture and be the hole of 100 ~ 800 microns, the connection rate of hole is greater than 97%, on the hole wall of hole, be formed with aperture and be the micropore of 5 ~ 100 microns, hole depth is 1 ~ 50 micron, porosity is 60 ~ 95%, this porous structure is conducive to the adhesion of bone and its cells and the transmission of nutrient, enough effective fixed cells, and then make its Differentiation and proliferation, for Growth of Cells provides a favourable growing environment, be conducive to realize the reparation of defective bone tissue.
Refer to Fig. 2, the preparation method of the porous bone support of an embodiment, comprises the steps:
Step S110: biological activity additive is dissolved in the first solvent, obtains the first solution.
Biological activity additive is selected from least one in chitosan, collagen, bone morphogenetic protein(BMP), icariin, Herba Epimedii.
The first solvent is selected from the one in Isosorbide-5-Nitrae-dioxane, acetonitrile, cyclohexane extraction, acetone, ethylene glycol, Ketohexamethylene and dichloromethane, is preferably Isosorbide-5-Nitrae-dioxane.The amount of the first solvent is fully dissolved biological activity additive.
Step S120: degradable metal, degradable inorganic matter and degradable polymer are dissolved in the second solvent, obtain the second solution.
Degradable metal is selected from the alloy of at least two kinds of formation in one in magnesium (Mg), ferrum (Fe), aluminum (Al), zinc (Zn), strontium (Sr) and manganese (Mn) or magnesium (Mg), ferrum (Fe), aluminum (Al), zinc (Zn), strontium (Sr), manganese (Mn).The metal or alloy that preferably purity is greater than 99%.
Degradable metal is that particle diameter is 100 ~ 500 object metal dusts, is preferably 300 orders.Individual in other embodiments, degradable metal can be also the thread metal of 1 ~ 500 micron for diameter.
Degradable inorganic matter is selected from least one in tricalcium phosphate (TCP), hydroxyapatite (HA), calcium phosphate, calcium silicates, magnesium oxide, magnesium hydroxide, magnesium chloride, magnesium carbonate, magnesium phosphate, magnesium silicate, ferrum oxide, titanium dioxide three-iron, hydrated ferric oxide., iron chloride and strontium carbonate.
It is the Powdered inorganic matter of 100 ~ 500 object that degradable inorganic matter is preferably particle diameter.
Degradable polymer is Porous poly-lactide-co-glycolide (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), poe, poly-anhydride, polyphosphazene or polyamino acid, or is the copolymer of at least two kinds of formation in Porous poly-lactide-co-glycolide (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), poe, poly-anhydride, polyphosphazene or polyamino acid.
The second solvent is selected from the one in Isosorbide-5-Nitrae-dioxane, acetonitrile, cyclohexane extraction, acetone, ethylene glycol, Ketohexamethylene and dichloromethane, is preferably Isosorbide-5-Nitrae-dioxane.The second solvent and the first solvent are selected same solvent.The amount of the second solvent is fully dissolved degradable metal, degradable inorganic matter and degradable polymer.
Degradable metal is carried out to mesh screen, and to obtain particle diameter be to be dried after 100 ~ 500 object powder.Degradable inorganic matter is carried out to mesh screen, and to obtain particle diameter be to be dried after 100 ~ 500 object powder.In mass ratio 1:1 ~ 3:1 ~ 5 will be dried after degradable metal, degradable inorganic matter and degradable polymer be dissolved in and in the second solvent, obtain the second solution.
Step S130: mix the first solution and the second solution, obtain mixed liquor.
Get the first appropriate solution and the second solution and mix, stirring spends the night obtains the mixed liquor of homogeneous phase, and in this mixed liquor, the mass ratio of biological activity additive and degradable polymer is 1:100 ~ 10000.
Above-mentioned mixed liquor is as the generating material of porous bone support, and biocompatibility to porous bone support, biological degradability, mechanical property, osseous tissue inductivity etc. produce material impact.
Chitosan, collagen, bone morphogenetic protein(BMP), icariin, Herba Epimedii etc. are as biological activity additive, these several materials are sustained release in porous bone support, can keep curative effect in bone defect for a long time, promote the growth of bone, and these several biological activity additives have the inductivity of the differentiation that promotes bone and its cells, be conducive to the differentiation of bone and its cells, thereby be conducive to repair deficiency osseous tissue.
Magnesium (Mg), ferrum (Fe), aluminum (Al), zinc (Zn), strontium (Sr) and manganese (Mn) are as the essential elements of osteogenesis, and the degradable metal that therefore contains this several elements can promote the growth of bone.
Degradable inorganic matter tricalcium phosphate (TCP), hydroxyapatite (HA), calcium phosphate, calcium silicates, magnesium oxide, magnesium hydroxide, magnesium chloride, magnesium carbonate, magnesium phosphate, magnesium silicate, ferrum oxide, titanium dioxide three-iron, hydrated ferric oxide., iron chloride and strontium carbonate have the similar material behavior of same osseous tissue and surface chemical property, are conducive to strengthen the biocompatibility of porous bone support.
The interpolation of degradable metal and degradable inorganic matter can strengthen the initial mechanical intensity of porous bone support, and the support of bone growth is provided.
Porous poly-lactide-co-glycolide, polylactic acid, polyglycolic acid, polycaprolactone, poe, poly-anhydride, polyphosphazene or polyamino acid, or these several degradable polymers of copolymer of at least two kinds of formation in Porous poly-lactide-co-glycolide, polylactic acid, polyglycolic acid, polycaprolactone, poe, poly-anhydride, polyphosphazene, polyamino acid play temporary supporting role in porous bone support, and with compound with biological activity additive, degradable metal and degradable inorganic matter, make bone support there is good biocompatibility and biodegradability.
In mixed liquor, the mass ratio of degradable metal, degradable inorganic matter and degradable polymer is 1: 1 ~ 3:1 ~ 5, the mass ratio of biological activity additive and degradable polymer is 1: 100 ~ 10000, can fully promote bone and its cells differentiation inductivity and enough mechanical strengths are provided.
Step S 140: with the damaged skeleton cross-section image of MEDCAD module statistical analysis in modular construction software Mimics, and measure the size of described damaged skeleton, according to analyzing and measurement result establishment cad model, the data that contain cad model described in derivation.
First carry out CT scan to obtain the gray level image of damaged skeleton cross sections at a certain distance, then carry out statistical analysis by the MEDCAD module in modular construction software Mimics, and the data of measuring damaged skeleton are to determine the size of porous bone support, as length, wide, high, according to statistic analysis result and measurement result, strengthen by contrast, thresholding, smoothing processing etc. create the cad model of personalized damaged skeleton, meet the porous bone support of the special skeletal structure of human body according to this cad model preparation, and can meet different patients' individual demand.The data that contain cad model derive with STL formatted file.STL form is an interface protocol of being formulated in 1988 by 3D SYSTEM company, is a kind of 3-D graphic file format for rapid prototyping technique service.
Modular construction software Mimics is the interactively medical image control system of Materialise company.Mimics is a system based on module, and it can be made to measure and meet client's human needs.In this software, allow different modules to offer all instrumental functions of medical image based on editor.MEDCAD module is the bridge between medical image (as CT, MRI image) and CAD design.MEDCAD converts user's scan-data to CAD object.
The situation that can react the most really damaged skeleton according to the cad model of the cross-section image of damaged skeleton and size foundation, prepares according to cad model the damaged bone repair demand that porous bone support can adapt to human body different parts.
Step S150: by delamination software, the described data that contain cad model are carried out to layering processing and obtain the data after layering, lift height is 0.05 ~ 0.2 millimeter, nozzle angle is 0 ~ 179 ° of conversion.
To contain the data of cad model, STL formatted file carries out layering processing, to determine in 3 D-printing process, and the height of injection of material, and the longitudinal aperture of porous bone scaffold.Layering is processed and is undertaken by the delamination software of low temperature rapid shaping instrument self, and lift height is 0.05 ~ 0.2 millimeter, and nozzle angle is 0 ~ 179 ° of conversion.
Layering obtains the data after layering after processing, and the data after this layering are exported as to CLI form.CLI(Common Layer Interface) form is a kind of form that European rapid shaping action tissue is supported.It attempts to overcome the limitation of STL form, can be adopted by various rapid prototyping systems.
Step S 160: mixed liquor is added in low temperature rapid shaping instrument, and by the data importing low temperature rapid shaping instrument after layering, at-40 ~-10 DEG C of temperature, carry out 3 D-printing according to the data after layering and form the cylinder porous bone support blank that cuboid, cylinder, square or cross section are rhombus, the spray webbing spacing of described 3 D-printing is 0.5 ~ 2 millimeter, spray head speed is 4 ~ 30 mm/second, and the liquid rate of outflow is 0.1 ~ 1 ml/min.
Mixed liquor is added in low temperature rapid shaping instrument (Tsing-Hua University, Tissueform-II), and data after the layering that step S150 is obtained, CLI formatted file imports in low temperature rapid shaping instrument.At-40 ~-10 DEG C, carry out 3 D-printing according to the data after layering and form the cylinder porous bone support blank that cuboid, cylinder, square or cross section are rhombus.In porous bone support blank, form multiple apertures and be the hole of 100 ~ 800 microns, the connection rate of hole is greater than 97%.
At-40 ~-10 DEG C, carry out 3 D-printing, be conducive to introducing and active preservation of biological activity additive, so that porous bone support has the inductivity of higher promotion bone and its cells differentiation.
The lift height of step S150 is 0.05 ~ 0.2 millimeter, nozzle angle is 0 ~ 179 ° of conversion, and the spray webbing spacing of 3 D-printing is preferably 0.5 ~ 2 millimeter, spray head speed is preferably 4 ~ 30 mm/second, the liquid rate of outflow is preferably 0.1 ~ 1 ml/min, and the aperture that can effectively control the hole of porous bone support blank is that 100 ~ 800 microns, connection rate reach more than 97%.
Step S170: porous bone support blank is processed after 5 minutes ~ 1 hour at-196 ~-40 DEG C of temperature, carried out vacuum drying and obtain porous bone support.
Obtaining after porous bone support blank, for the hole wall at hole forms micropore, to improve specific surface area and the roughness of hole wall, mentioning the adhesiveness of cell at porous bone support.Porous bone support blank is processed 5 minutes ~ 1 hour at-196 ~-40 DEG C of temperature, made the first solvent and the second solvent need to form the crystallization of corresponding size according to the design of the micropore of hole wall, then carry out vacuum drying to remove the first solvent and the second solvent.
Vacuum drying step is that the porous bone support blank after-196 ~-40 DEG C of Temperature Treatment is put into freezer dryer, below vacuum 20Pa, is warming up at 10 ~ 30 DEG C and is dried 48 hours with the programming rate of 1 ~ 10 DEG C/h.Adopt 1 ~ 10 DEG C/h of lower baking temperature of programming rate and 10 ~ 30 DEG C comparatively slowly, to keep the activity of biological activity additive.
After vacuum drying, in the hole wall of the hole of porous bone support blank, form micropore, the aperture of micropore is that 5 ~ 100 microns, the degree of depth are 1 ~ 50 micron.The porosity of the porous bone support finally obtaining is 60 ~ 95%.
Finally obtain being shaped as the porous bone support that cuboid, cylinder, square or cross section are the cylinder of rhombus, the porosity of porous bone support is 60 ~ 95%, the pore size of hole be 100 ~ 800 microns, the connection rate in hole more than 97%, it is that 5 ~ 100 microns, the degree of depth are the micropore of 1 ~ 50 micron that hole wall is distributed with a large amount of apertures.Porosity is 60 ~ 95%, aperture is nutrition transmission and the metabolic demand that the supporting structure of 100 ~ 800 microns can meet bone and its cells growth, on hole wall, the micropore of 5 ~ 100 μ m has increased specific surface area and the roughness of hole wall, increase the contact area of cell and porous bone rack surface, the migration of block cell, play fixed cell, promote osteoblast to adhere to, the effect of propagation and differentiation.The connection rate in hole is up to more than 97%, and good hole link is conducive to growing into of osseous tissue and vascular tissue, is convenient to the conveying of nutrient substance and the excretion of products of cellular metabolism, ensures the conduction of osseous tissue.
The preparation method of above-mentioned porous bone support is by arranging the parameter of suitable layering processing, parameter, K cryogenic treatment and the vacuum drying parameter of 3 D-printing, prepares pore size, the porosity of porous bone support, pore size, the degree of depth etc. of micropore to control.Preferably, adopt that the preparation method of above-mentioned porous bone support can prepare that aperture is that 300 ~ 500 microns, porosity are 80 ~ 90%, the pore size of micropore is the porous bone support of 20 ~ 30 microns of 5 ~ 20 microns, hole depth.The method of 3 D-printing and low temperature moulding has with short production cycle and low cost and other advantages, and low temperature moulding is conducive to keep the activity of biological activity additive.
The preparation method of above-mentioned porous bone support is set up personalized bone support cad model according to skeleton cross-section image and skeleton size, can meet the needed biology of different implant sites of bone and the requirement of mechanics, then the pore size that utilizes low temperature rapid shaping technique to realize the hole of bone support is 100 ~ 800 and the porosity regulation and control that are 60 ~ 95%, and realize the regulation and control of microcellular structure that form 5 ~ 100 μ m on hole wall in conjunction with phase detachment technique, prepare the porous bone support with 3 D stereo pleated structure of design in advance, this porous bone support can meet the psychological need of cell and tissue growth, be conducive to realize the reparation of defective bone tissue.
The preparation method of above-mentioned porous bone support combines modular construction software design with low temperature rapid prototyping system and phase detachment technique, Trinity preparation meets the porous bone support of the special skeletal structure of human body, better to adapt to the interior environment of implant site, be more conducive to the reparation of bone defect.
It is below specific embodiment 1
Embodiment 1
1, at room temperature, 1 part of collagenolysis is obtained in the first solution in Isosorbide-5-Nitrae-dioxane; Be 1 in mass ratio: it is that 300 object metal magnesium powders, 25 parts of particle diameters are that 300 object TCP and 100 parts of PLGA are dissolved in 1 that 1:4 takes 25 parts of particle diameters, in 4-dioxane, obtain the second solution, mix the first solution and the second solution, stirring spends the night obtains the mixed liquor of homogeneous phase.
2, with the MEDCAD module statistical analysis shank defect of tibial skeleton cross-section image in modular construction software Mimics, and measure the size of described damaged skeleton, create cad model according to described analysis and measurement result, the cuboid porous bone support that cad model is 3 × 3 × 4cm for length × wide × height, the data that contain this cad model are exported as to STL formatted file, carry delamination software with low temperature rapid shaping instrument again and carry out layering processing to determine the thickness of every one deck, i.e. lift height.Lift height is for for 0.12mm, and nozzle angle is 0 °/90 ° conversion, prints one decks by 0 ° or 90 °, then, by one deck under 90 ° or 0 ° of printing, so converts, and the data after layering are exported as to CLI formatted file.
3, above-mentioned mixed liquor is poured in low temperature rapid shaping instrument, according to above-mentioned CLI formatted file, spray webbing spacing being set is 1.2mm, spray head speed is 21mm/s, the liquid rate of outflow is 1ml/min, at-25 DEG C, carry out 3 D-printing and form porous bone support blank, the hole of this porous bone support blank is circular, and aperture is that 400 μ m, initial porosity are 68%, connection rate in hole is 98%.
4, above-mentioned porous bone support blank being placed in to-40 DEG C processed after 24 minutes, be placed in freezer dryer, vacuum is 10Pa, programming rate is 1 DEG C/h, be warming up to 20 DEG C, lyophilization obtains hole aperture after 48 hours is that 400 μ m, final porosity are 81%, hole wall is distributing, and a large amount of apertures are the porous bone support of 20 ~ 40 μ m micropores, the hole depth 14 μ m of micropore.
Fig. 3 is the surface-element analysis chart of obtained porous bone support, and as seen from Figure 3, TCP (A) and Mg (B) are contained in the surface of porous bone support.
Fig. 4 to Fig. 8 is the scanning electron microscope (SEM) photograph of obtained porous bone support, can be found out by Fig. 4 to Fig. 8, the porous bone support that obtains forms multiple holes, on the hole wall in hole, form again multiple micropores, hole wall has larger specific surface area and roughness, and this porous bone support is the pore network structure of porous and internal run-through.
Fig. 9 is the scanning electron microscope (SEM) photograph of normal spongy bone.Comparison diagram 8 and Fig. 9 are known, and prepared to obtain porous bone supporting structure comparatively approaching with normal cancellous bone structure.
Embodiment 2
1, at room temperature, 1 part of bone morphogenetic protein(BMP) is dissolved in acetonitrile and is obtained in the first solution; Be that 500 object metal iron powders, 100 parts of particle diameters are that 500 object TCP and 500 parts of PCL are dissolved in acetonitrile and obtain the second solution for 1:1:5 takes 100 parts of particle diameters in mass ratio, mix the first solution and the second solution, stirring spends the night obtains the mixed liquor of homogeneous phase.
2, with the damaged hand ulna of the MEDCAD module statistical analysis skeleton cross-section image in modular construction software Mimics, and measure the size of described damaged skeleton, create cad model according to described analysis and measurement result, cad model is diameter 2cm, the cylinder porous bone support of high 4cm, the data that contain this cad model are exported as to STL formatted file, carry delamination software with low temperature rapid shaping again and carry out layering processing, lift height is 0.1mm, nozzle angle is 0/60 ° of conversion, print one deck by 0 ° or 60 °, then by one deck under 60 ° or 0 ° of printing, so conversion, data after layering are derived to CLI formatted file.
3, above-mentioned even phase solution is poured in low temperature rapid shaping instrument, according to above-mentioned CLI formatted file, it is 1mm that spray webbing spacing is set, spray head speed is 10mm/s, the liquid rate of outflow is 1.5ml/min, at-30 DEG C, carry out 3 D-printing and form porous bone support blank, the duct of this porous bone support blank is rhombus, and the aperture in duct is that 250 μ m, initial porosity are 70%, connection rate in hole is 97%.
4, above-mentioned porous bone support blank is placed at-196 DEG C and is processed after 10min, be placed in freezer dryer, vacuum is 10Pa, and programming rate is 2 DEG C/h, is warming up to 30 DEG C, lyophilization 48h aftershaping.Obtain aperture and be 250 μ m, final porosity is 86%, hole wall a large amount of apertures that distributing are the porous bone support of 5 ~ 10 μ m micropores, the hole depth 6 μ m of micropore.
Example 3
1, at room temperature, 1 part of icariin is dissolved in cyclohexane extraction and is obtained in the first solution; Be 1 in mass ratio: it is that 100 object Preparation of Metallic Strontium powder, 500 parts of particle diameters are that 100 object HA and 1000 parts of PLLA are dissolved in and in cyclohexane extraction, obtain the second solution that 1:2 takes 500 parts of particle diameters, mix the first solution and the second solution, stirring spends the night obtains the mixed liquor of homogeneous phase.
2, with the MEDCAD module statistical analysis hand Ulna injuries skeleton cross-section image in modular construction software Mimics, and measure the size of described damaged skeleton, create cad model according to described analysis and measurement result, the cylinder porous support that cad model is rhombus for the cross section that length × wide × height is 2 × 2 × 3cm, the data that contain this cad model are exported as to STL formatted file, carry delamination software with low temperature rapid shaping again and carry out layering processing, lift height is 0.08mm, nozzle angle is 60 °/135 ° conversion, print one deck by 60 ° or 135 °, then by one deck under 135 ° or 60 ° of printings, so conversion, data after layering are exported as to CLI formatted file.
3, above-mentioned even phase solution is poured in low temperature rapid shaping instrument, according to above-mentioned CLI formatted file, it is 0.8mm that spray webbing spacing is set, spray head speed is 15mm/s, the liquid rate of outflow is 1ml/min, carries out 3 D-printing and form porous bone support blank at-45 DEG C, and the duct of this porous bone support blank is rhombus, the aperture in duct is 200 μ m, and initial porosity is 73%, hole connection rate reaches 100%.
4, above-mentioned porous bone support blank is placed in to pre-cooling at-196 DEG C and, after 1 hour, is placed in freezer dryer, vacuum is 10Pa, and programming rate is 5 DEG C/h, is warming up to 10 DEG C, lyophilization 48h aftershaping.Obtain aperture and be 200 μ m, final porosity and be 88%, connection rate in hole is 97%, the hole wall aperture that distributing is the porous bone support of 5 ~ 10 μ m micropores, the hole depth 6 μ m of micropore.
The above embodiment has only expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (7)
1. a porous bone support, it is characterized in that, described porous bone support is by biological activity additive, degradable metal, degradable inorganic matter and degradable polymer form, described porous bone support be shaped as cuboid, cylinder or cross section are the cylinder of rhombus, on described porous bone support, form multiple holes, the connection rate of hole is greater than 97%, on the hole wall of described hole, be formed with multiple micropores, the aperture of described hole is 100～800 microns, the aperture of described micropore is 5～100 microns, 1～50 micron of hole depth, the porosity of described porous bone support is 60～95%,
Described biological activity additive is selected from least one in chitosan, collagen, icariin and Herba Epimedii;
Described degradable metal is selected from the alloy of at least two kinds of formation in a kind of or ferrum in magnesium, ferrum, aluminum, zinc, strontium and manganese, aluminum, zinc, strontium, manganese;
Described degradable inorganic matter is selected from least one in hydroxyapatite, calcium phosphate, calcium silicates, magnesium oxide, magnesium hydroxide, magnesium chloride, magnesium carbonate, magnesium phosphate, magnesium silicate, ferrum oxide, titanium dioxide three-iron, hydrated ferric oxide., iron chloride and strontium carbonate;
Described degradable polymer is polylactic acid, polyglycolic acid, polycaprolactone, poe, poly-anhydride, polyphosphazene or polyamino acid, or is the copolymer of at least two kinds of formation in Porous poly-lactide-co-glycolide, polylactic acid, polyglycolic acid, polycaprolactone, poe, poly-anhydride, polyphosphazene or polyamino acid;
The mass ratio of described degradable metal, degradable inorganic matter and degradable polymer is 1:1～3:1～5, and the mass ratio of described biological activity additive and degradable polymer is 1:100～10000.
2. porous bone support according to claim 1, is characterized in that, described porosity is 80～90%, and the aperture of described hole is 300～500 microns, and the aperture of described micropore is 20～30 microns of 5～20 microns, hole depth.
3. a preparation method for porous bone support, is characterized in that, comprises the steps:
Biological activity additive is dissolved in the first solvent, obtains the first solution;
Degradable metal, degradable inorganic matter and degradable polymer are dissolved in the second solvent, obtain the second solution;
Mix described the first solution and the second solution, obtain mixed liquor;
With the damaged skeleton cross-section image of MEDCAD module statistical analysis in modular construction software Mimics, and measure the size of described damaged skeleton, create cad model according to described analysis and measurement result, derive the data that contain described cad model;
By delamination software, the described data that contain cad model are carried out to layering processing and obtain the data after layering, lift height is 0.05～0.2 millimeter, and nozzle angle is 0～179 ° of conversion;
Described mixed liquor is added in low temperature rapid shaping instrument, and by the data importing low temperature rapid shaping instrument after described layering, at-40～-10 DEG C of temperature, carry out 3 D-printing according to the data after described layering and form cuboid, cylinder or cross section are the cylinder porous bone support blank of rhombus, the spray webbing spacing of described 3 D-printing is 0.5～2 millimeter, spray head speed is 4～30 mm/second, the liquid rate of outflow is 0.1～1 ml/min, in described porous bone support blank, be formed with multiple apertures and be the hole of 100～800 microns, the connection rate of hole is greater than 97%,
Described porous bone support blank is processed after 5 minutes～1 hour at-196～-40 DEG C of temperature, carry out vacuum drying and obtain porous bone support, on the hole wall of the hole of described porous bone support, be formed with multiple micropores, the aperture of described micropore is that 5～100 microns, hole depth are 1～50 micron, and the porosity of described porous bone support is 60～95%;
Described biological activity additive is selected from least one in chitosan, collagen, icariin, Herba Epimedii;
Described degradable metal is selected from the alloy of at least two kinds of formation in a kind of or ferrum in magnesium, ferrum, aluminum, zinc, strontium and manganese, aluminum, zinc, strontium, manganese;
Described degradable inorganic matter is selected from least one in hydroxyapatite, calcium phosphate, calcium silicates, magnesium oxide, magnesium hydroxide, magnesium chloride, magnesium carbonate, magnesium phosphate, magnesium silicate, ferrum oxide, titanium dioxide three-iron, hydrated ferric oxide., iron chloride and strontium carbonate;
Described degradable polymer is polylactic acid, polyglycolic acid, polycaprolactone, poe, poly-anhydride, polyphosphazene or polyamino acid, or is the copolymer of at least two kinds of formation in Porous poly-lactide-co-glycolide, polylactic acid, polyglycolic acid, polycaprolactone, poe, poly-anhydride, polyphosphazene or polyamino acid;
The mass ratio of described degradable metal, degradable inorganic matter and degradable polymer is 1:1～3:1～5, and the mass ratio of described biological activity additive and degradable polymer is 1:100～10000.
4. the preparation method of porous bone support according to claim 3, is characterized in that, described degradable metal is that particle diameter is that 100～500 object metal dusts or diameter are the thread metal of 1～500 micron.
5. the preparation method of porous bone support according to claim 3, is characterized in that, described degradable inorganic matter is that particle diameter is the Powdered inorganic matter of 100～500 object.
6. the preparation method of porous bone support according to claim 3, is characterized in that, described the first solvent and the second solvent are selected from the one in Isosorbide-5-Nitrae-dioxane, acetonitrile, cyclohexane extraction, acetone, ethylene glycol, Ketohexamethylene and dichloromethane.
7. the preparation method of porous bone support according to claim 3, is characterized in that, described vacuum drying step is below vacuum 20Pa, at 10～30 DEG C of temperature dry 12～48 hours.
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