CN118340936B - Repair factor composite bone supporting material and preparation method thereof - Google Patents
Repair factor composite bone supporting material and preparation method thereof Download PDFInfo
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- CN118340936B CN118340936B CN202410764880.3A CN202410764880A CN118340936B CN 118340936 B CN118340936 B CN 118340936B CN 202410764880 A CN202410764880 A CN 202410764880A CN 118340936 B CN118340936 B CN 118340936B
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Abstract
The invention discloses a repair factor composite bone supporting material and a preparation method thereof, belonging to the technical field of biomedical materials; the invention provides a method for loading polylactic acid and KGN composite fiber on the surface of alkali-heat activated titanium alloy in an electrostatic spinning mode, so as to realize the loading and slow release of the medicine; adding mesoporous silica obtained by performing surface activation treatment by a plasma immersion ion implantation technology, providing bioactive sites, and promoting adsorption and proliferation of bone cells; zinc ions are introduced, so that the antibacterial property is improved; the silk fibroin obtained by adding methacrylate modification is soaked in oxidized icariin solution, schiff base reaction is generated between amino groups of the silk fibroin and aldehyde groups of oxidized icariin, so that a hydrophilic three-dimensional network structure gel structure is formed, titanium alloy is stably coated, corrosion resistance, antibacterial property and anti-inflammatory property are improved, mechanical property and biocompatibility of the titanium alloy in a body are improved, and the technical effect of slowly releasing repair factors is achieved.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to a repair factor composite bone supporting material and a preparation method thereof.
Background
As the population ages, there is a rapid increase in the incidence of bone defects or fractures due to rheumatoid arthritis, osteoporosis, limb trauma or natural deformity, and thus there is a need for artificial implants to replace for repairing, replacing or reconstructing bone structures; orthopedic implant materials play a critical role in orthopedic surgery, and are implanted into the human body to promote fracture healing and bone cell growth, and ideal orthopedic implant materials should generally have suitable mechanical properties, connected porous structures, good hydrophilicity, suitable degradation resistance and excellent bone conductivity, as well as good antibacterial ability.
Common orthopedic implant materials include metal alloys, bioceramics, natural polymer materials, artificial polymer materials, bioactive glass, etc., which have good mechanical properties and can be used as the first choice of orthopedic support materials, and metal alloys include titanium, magnesium, zinc and alloys thereof, which are widely used as implantable support materials for orthopedic, orthopedic and dental applications due to their excellent mechanical properties, corrosion resistance and biocompatibility; in order to further improve the biological properties of orthopedic support materials, repair growth factors are also often introduced into orthopedic implant materials as important participants in the bone formation process to improve the effects of bone repair, such as Vascular Endothelial Growth Factor (VEGF) and bone morphogenic protein-2 (BMP-2), which are commonly used, which are capable of inducing angiogenesis, activating osteogenesis-related signal pathways and finally promoting bone regeneration, however, these growth factors are expensive and unstable, icariin is a main bioactive ingredient of the traditional Chinese medicine icariin, has remarkable vascular and anti-inflammatory effects, and can be added into bone support materials as repair growth factors.
However, the surface of the original titanium alloy is biologically inert, can not fully induce or stimulate specific cell behaviors, is unfavorable for the adhesion and growth of bone cells, lacks the osteogenesis, vascularization and anti-inflammatory properties, can reduce the growth capacity of new bone tissues, thereby increasing the risk of failure of bone repair, finally causing the problems of poor integration with surrounding bone tissues, blocking the formation of new bones or slow osseointegration rate and the like, and seriously affecting the success rate of orthopedic implantation surgery; therefore, how to provide a titanium alloy-based orthopedic support material with good mechanical properties and biocompatibility, wear resistance, anti-inflammatory and antibacterial properties, promoting osteogenesis, and slow release of repair factors is a problem to be solved by those skilled in the art.
Disclosure of Invention
Aiming at the situation, in order to overcome the defects of the prior art, the invention provides a repair factor composite bone supporting material and a preparation method thereof, and aims to solve the problems that the mechanical compatibility of titanium alloy is poor, the surface inertia is unfavorable for the adhesion of osteoblasts, the anti-inflammatory and antibacterial properties are poor, the composite bone supporting material is easy to wear and the repair factor is released in a large amount rapidly; mesoporous silica obtained by adding a plasma immersion ion implantation technology for surface activation treatment is provided with a bioactive site, so that adsorption and proliferation of bone cells are promoted; after adding the silk fibroin obtained by modification of the methacrylate, soaking the silk fibroin in oxidized icariin solution, and performing Schiff base reaction between amino groups of the silk fibroin and aldehyde groups of oxidized icariin, thereby forming a hydrophilic three-dimensional network structure gel structure, stably coating the titanium alloy, improving the wear resistance, the antibacterial property and the anti-inflammatory property, further realizing the technical effects of improving the mechanical property and the biocompatibility of the titanium alloy in vivo and slowly releasing the repair factors.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: the invention provides a repair factor composite bone supporting material and a preparation method thereof, wherein the preparation method of the repair factor composite bone supporting material specifically comprises the following steps:
S1, selecting medical titanium alloy, extruding and forming to obtain a titanium plate or bar, sequentially polishing samples by using silicon sand paper with the model of 800 meshes, 1000 meshes, 1500 meshes and 2000 meshes, soaking the samples in 1.0-1.8mol/L sodium hydroxide solution for 20-24 hours at 50-60 ℃, sequentially carrying out ultrasonic vibration cleaning by using ethanol, acetone and deionized water for 30-40 minutes, and drying for later use;
S2, dissolving KGN in acetone to obtain KGN solution; dissolving polylactic acid in a mixed solvent of acetone and N, N-dimethylformamide in a volume ratio of 6:1 to obtain a polylactic acid solution; mixing KGN solution and polylactic acid solution to obtain spinning solution for standby;
S3, applying external voltage to the spinning solution obtained in the step S2 through an electrostatic spinning process to form jet flow under the action of an external electric field, and receiving the jet flow by utilizing the titanium alloy treated in the step S1 to finally solidify the jet flow into nano fibers on the surface of the titanium alloy to obtain the titanium alloy loaded with polylactic acid and KGN composite fibers for later use;
S4, adding natural cocoons into a sodium carbonate aqueous solution with the concentration of 0.05mol/L, boiling for 20-30min at the temperature of 100 ℃, washing with cold water, repeating the same treatment for 2-3 times, drying to obtain degummed silk, adding a lithium bromide aqueous solution with the concentration of 9.2mol/L, dissolving for 1-2h at the temperature of 65-75 ℃, dialyzing for 12h to obtain a silk fibroin solution, adding glycidyl methacrylate, stirring for 3-5h, dialyzing for 24h to obtain a methacrylate modified silk fibroin solution for later use;
s5, mixing the titanium alloy treated in the step S3 with modified mesoporous silica, adding a zinc nitrate hexahydrate solution with the concentration of 0.5mol/L for soaking treatment, standing at room temperature for 24 hours, freeze-drying, adding the methacrylate modified silk fibroin solution obtained in the step S4, uniformly stirring at 4 ℃, and freeze-drying at-2 ℃ to obtain a pretreated bone supporting material for later use;
S6, dissolving oxidized icariin in an ethanol water solution with the mass fraction of 50-60% to obtain an oxidized icariin solution with the concentration of 0.5-3mg/mL, soaking the pretreated bone supporting material obtained in the S5 in the oxidized icariin solution, reacting for 20-24 hours at the temperature of 4 ℃, washing with deionized water, and freeze-drying to obtain the repair factor composite bone supporting material.
Preferably, in S2, the addition amount of KGN in acetone is 0.01-0.02g/mL;
Preferably, in S2, the addition amount of the polylactic acid in the mixed solvent of acetone and N, N-dimethylformamide is 0.2-0.3g/mL;
preferably, in S2, the volume ratio of the KGN solution to the polylactic acid solution is 1-2:10;
Preferably, in S3, the conditions of the electrospinning process: the external voltage is 10-20kv, the propulsion rate is 1.2-1.6mL/h, the distance between the injector nozzle and the titanium alloy is 15cm, the rotating speed of the roller is 1000-3000rpm, and the time is 4-6min;
preferably, in S3, the total weight of the polylactic acid and KGN composite fiber accounts for 1-2% of the total dry weight of the bone supporting material;
preferably, in S4, the addition amount of the natural silkworm cocoons in the sodium carbonate aqueous solution is 20-24g/L;
preferably, in S4, the addition amount of the degummed silk in the lithium bromide aqueous solution is 0.2-0.24g/mL;
preferably, in S4, the mass-to-volume ratio of the degummed silk to the glycidyl methacrylate is 20-24g:5-7mL;
The silk fibroin has excellent biocompatibility, and stem cells, osteoblasts and macrophages can be adhered and grown on the silk fibroin material; the collagen or hyaluronic acid-based tissue repair material has low immunogenicity, natural anti-inflammatory property, is suitable for regeneration and repair of various tissues, and compared with other tissues, the collagen or hyaluronic acid-based tissue repair material has the advantages that the bone tissue repair takes longer time, the degradation performance matched with bone regeneration can improve the tissue repair quality, the collagen or hyaluronic acid-based tissue repair material has higher degradation rate, and is more suitable for repair of soft tissues, the natural silk is slowly absorbed in the body, the degradation time is generally more than half a year, and the degradation performance is better matched with the bone tissue; the silk fibroin can be used as a carrier to realize the high-efficiency loading and the controlled release of water-soluble and fat-soluble macromolecular or micromolecular medicaments and different types of growth factors.
Preferably, in S5, the mass-to-volume ratio of the titanium alloy, the modified mesoporous silica and the methacrylate modified silk fibroin solution is 20-30g:15-35g:100mL;
preferably, in S5, the modified mesoporous silica is obtained by performing surface activation treatment on mesoporous silica by a plasma immersion ion implantation technology;
Preferably, the treatment conditions are: argon is injected into the mesoporous silica by adopting a GPI-100 gas injector, the argon flow is 20-40sccm, the radio frequency is 8000-10000W, the pulse voltage is-20 to-15 kV, the working pressure is 1X 10 -2-10×10- 2 Pa, the pulse width is 80-120 mu s, the pulse frequency is 40-60Hz, and the treatment time is 8-10min; the mesoporous silica nanoparticle is of the type Sigma-Aldrich 748161, the particle size is 200nm, and the pore size is 4nm;
Preferably, in S6, the preparation method of oxidized icariin specifically includes the following steps:
Dissolving icariin in absolute ethyl alcohol to obtain an icariin solution; dissolving sodium periodate in distilled water to obtain sodium periodate aqueous solution, mixing icariin solution and sodium periodate aqueous solution, reacting for 3-5h under the condition of light-proof ice bath, centrifuging for 15-20min at 1500-4500rpm, dialyzing for 2-3d with dialysis bag with molecular weight cutoff of 14kD, and lyophilizing dialysate to obtain oxidized icariin;
preferably, the addition amount of the icariin in the absolute ethyl alcohol is 0.2-0.25g/mL;
Preferably, the mass volume ratio of the sodium periodate to the distilled water is 0.12-0.16g/mL;
Icariin is an active ingredient of a traditional Chinese medicine, has the effects of tonifying liver and kidney, dispelling wind and dampness, strengthening bones and muscles, improving immunity, resisting aging, inhibiting tumors and the like in the field of traditional Chinese medicines, and the prior literature reports that the icariin can effectively promote BMSCs to directionally differentiate into chondrocytes and can increase protein products specific to the chondrocytes.
Preferably, the medical titanium alloy comprises the following components in percentage by mass: zn:2.5-4%, ca:1.2-2.1%, sr:0.12-0.24%, al:0.05-0.08%, and the balance being titanium.
The invention provides a repair factor composite bone supporting material prepared by the preparation method.
The beneficial effects obtained by the invention are as follows:
The invention takes medical titanium alloy as a base material, loads polylactic acid and KGN composite fiber on the surface of medical titanium alloy after alkali thermal activation in an electrostatic spinning mode to form a polymer coating, adds mesoporous silicon dioxide obtained by surface activation treatment by a plasma immersion ion implantation technology, mixes uniformly, soaks in zinc nitrate hexahydrate solution, adds in silk fibroin solution obtained by methacrylate modification to obtain a pretreated bone supporting material, soaks the pretreated bone supporting material in icariine oxide solution to form a hydrophilic three-dimensional network structure gel structure, coats the titanium alloy stably, and obtains the titanium alloy with good mechanical property, compatibility, wear resistance and anti-inflammatory antibacterial property, promoting the adhesion and growth of bone cells, and slowly releasing the repair factor composite bone supporting material of oxidized icariin; the medical titanium alloy is activated in alkali liquor, so that more hydroxyl groups are exposed on the surface of the medical titanium alloy, on one hand, the hydroxyl groups can improve the hydrophilicity of the medical titanium alloy and promote the adhesion and proliferation of bone cells, thereby improving the compatibility of the medical titanium alloy material and biological tissues, reducing the rejection reaction of the tissues to the metal alloy material, and being beneficial to reducing inflammatory reaction and promoting wound healing; on the other hand, the hydroxyl group is negatively charged, and can be combined with Ca 2+ with positive charge in physiological fluid to form amorphous calcium phosphate, so that the osseointegration capability of the orthopedic implant material is improved initially, and the adsorption of polylactic acid and KGN on the surface of the titanium alloy is promoted; Polylactic acid is an absorbable high polymer material, has good biocompatibility, promotes tendon repair, and KGN (Kartogenin) is used as a micromolecular cartilage differentiation inducer, can induce MSC (mesenchymal stem cells) to differentiate into chondrocytes, has ideal induction effect, is favorable for promoting the regeneration of chondrocytes, has the synergistic effect of polylactic acid and KGN, and can improve the repair and regeneration of bone cells; The mesoporous silica is subjected to surface activation treatment by a plasma immersion ion implantation technology to obtain modified mesoporous silica, the specific surface area of the modified mesoporous silica is increased, the roughness and the porosity of the modified mesoporous silica are improved, after the modified mesoporous silica is mixed with a titanium alloy material, the particle size of the modified mesoporous silica is smaller and is nanoscale, the treated titanium alloy surface has certain viscosity due to the coating of polylactic acid, meanwhile, the nanofiber forms a pore structure to fix a part of the modified mesoporous silica, under the winding action of methacrylate modified silk fibroin, the modified mesoporous silica and the treated titanium alloy material can be physically combined, Thereby forming a pre-treated bone supporting material; soaking in hexahydrate zinc nitrate solution to improve the antibacterial property of the bone supporting material; The methacrylate is used for modifying the silk fibroin, improving the solubility, biocompatibility and blood compatibility of the silk fibroin, introducing double bonds, providing a good cell adhesion matrix for surrounding tissues, promoting migration and proliferation of bone cells, accelerating the repair and regeneration process of bone tissues, generating Schiff base reaction between amino groups of the silk fibroin and aldehyde groups of oxidized icariin, tightly connecting the amino groups of the silk fibroin and aldehyde groups of oxidized icariin, forming hydrogel with a three-dimensional porous structure, generating amidation reaction between carboxyl groups of the silk fibroin and amino groups in the bone tissue matrix, forming crosslinking again, improving the porosity of the hydrogel on the surface of titanium alloy, promoting the deposition of hydroxyapatite, The icariin serving as the repairing factor is slowly released, and the icariin serving as the active ingredient of the traditional Chinese medicinal material has anti-inflammatory performance, so that the infection of bone tissues can be avoided; as multiple cross links are formed, the adhesion between the hydrogel and damaged bone tissues is facilitated, and the stability and the gel strength of the hydrogel material are improved, so that the mechanical property of the bone supporting material is improved.
Drawings
FIG. 1 is a graph showing the tensile strength and elongation at break test results of the bone supporting materials prepared in examples 1 to 3 and comparative examples 1 to 4 according to the present invention.
FIG. 2 is a graph showing the results of the compressive strength and elastic modulus test of the bone supporting materials prepared in examples 1 to 3 and comparative examples 1 to 4 according to the present invention.
Fig. 3 is a graph showing the results of corrosion resistance test of the bone supporting materials prepared in example 1 and comparative examples 1 and 3 of the present invention.
FIG. 4 is a graph showing the results of cell adhesion performance test of the bone supporting materials prepared in examples 1 to 3 and comparative examples 1 to 4 according to the present invention.
FIG. 5 is a graph showing the results of antibacterial property test of the bone supporting materials prepared in examples 1 to 3 and comparative examples 4 and 5 according to the present invention.
FIG. 6 is a graph showing the results of anti-inflammatory property tests of the bone supporting materials prepared in examples 1 to 3 and comparative examples 3 and 4 according to the present invention.
Fig. 7 is a graph showing the results of the bone supporting material repair factor release test prepared in example 1 and comparative examples 3 and 4 according to the present invention.
Fig. 8 is a scanning electron microscope image of the surface morphology of the bone supporting material prepared in example 1 of the present invention.
FIG. 9 is a scanning electron microscope image of the bone supporting material prepared in example 1 of the present invention after mineralization in a simulated body fluid for 28 days.
The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate the invention and together with the embodiments of the invention, serve to explain the invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which it is evident that the embodiments described are only some, but not all embodiments of the invention; all other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the present application. The preferred methods and materials described herein are illustrative only and should not be construed as limiting the application.
The experimental methods in the following examples are all conventional methods unless otherwise specified; the test materials used in the examples described below, unless otherwise specified, were purchased from commercial sources.
Example 1
The preparation method of the repair factor composite bone supporting material specifically comprises the following steps:
S1, selecting a disc-shaped medical titanium alloy with the diameter of 10.0mm and the thickness of 0.25mm, sequentially polishing samples by using silicon sand paper with the model of 800 meshes, 1000 meshes, 1500 meshes and 2000 meshes, soaking the samples in a sodium hydroxide solution with the mol/L of 1.0 at 50 ℃ for 20 hours, sequentially carrying out ultrasonic vibration cleaning by using ethanol, acetone and deionized water for 30 minutes, and drying for later use;
S2, dissolving 10mgKGN in 1mL of acetone to obtain KGN solution; 2.0g of polylactic acid is dissolved in 10mL of mixed solvent of acetone and N, N-dimethylformamide with the volume ratio of 6:1 to obtain polylactic acid solution; mixing 1mLKGN solution and 10mL polylactic acid solution to obtain spinning solution for standby;
s3, applying external voltage of 10kv and a propulsion rate of 1.2mL/h to the spinning solution obtained in the step S2 through an electrostatic spinning process, forming jet flow under the action of an external electric field, receiving the jet flow by utilizing the titanium alloy treated in the step S1, wherein the distance between a nozzle of an injector and the titanium alloy is 15cm, the rotating speed of a roller is 1000rpm, and the time is 4min, and finally solidifying the jet flow on the surface of the titanium alloy into nano fibers to obtain the titanium alloy loaded with polylactic acid and KGN composite fibers for later use;
s4, adding 20g of natural silk cocoons into 1L of sodium carbonate aqueous solution with the concentration of 0.05mol/L, boiling for 20min at the temperature of 100 ℃, flushing with cold water, repeating the same treatment for 2 times, drying to obtain degummed silk, adding 100mL of lithium bromide aqueous solution with the concentration of 9.2mol/L into 20g of degummed silk, dissolving for 1h at the temperature of 65 ℃, dialyzing for 12h to obtain a silk fibroin solution, adding 5mL of glycidyl methacrylate, stirring for 3h, and dialyzing for 24h to obtain a methacrylate modified silk fibroin solution for later use;
S5, mixing 20g of the titanium alloy treated in the S3 with 15g of modified mesoporous silica, adding a zinc nitrate hexahydrate solution with the concentration of 0.5mol/L for soaking treatment, standing at room temperature for 24 hours, freeze-drying, adding a methacrylate modified silk fibroin solution obtained by 100mLS4, uniformly stirring at 4 ℃, and freeze-drying at-2 ℃ to obtain a pretreated bone supporting material for later use;
s6, dissolving 50mg of oxidized icariin in 100mL of ethanol water solution with the mass fraction of 50% to obtain oxidized icariin solution, soaking the pretreated bone supporting material obtained in the S5 in the oxidized icariin solution, reacting for 20 hours at the temperature of 4 ℃, washing with deionized water, and freeze-drying to obtain the repair factor composite bone supporting material.
The mesoporous silica adopted in the embodiment is mesoporous silica nano particles, the model is Sigma-Aldrich 748161, the particle size is 200nm, the pore diameter is 4nm, and the modified mesoporous silica is obtained by performing surface activation treatment on the mesoporous silica by a plasma immersion ion implantation technology; the treatment conditions are as follows: and (3) injecting argon into the mesoporous silicon dioxide by using a GPI-100 gas injector, wherein the argon flow is 20sccm, the radio frequency is 8000W, the pulse voltage is-20 kV, the working pressure is 1X 10 -2 Pa, the pulse width is 80 mu s, the pulse frequency is 40Hz, and the treatment time is 8min.
The preparation method of the oxidized icariin specifically comprises the following steps:
10g of icariin is dissolved in 50mL of absolute ethyl alcohol to obtain an icariin solution; 6g of sodium periodate is dissolved in 50mL of distilled water to obtain a sodium periodate aqueous solution, icariine solution and the sodium periodate aqueous solution are mixed and reacted for 3h under the condition of light-proof ice bath, the mixture is centrifuged for 20min at 2000rpm, a dialysis bag with the molecular weight cutoff of 14kD is used for dialysis for 68h, and the dialyzate is freeze-dried to obtain oxidized icariine.
The invention provides a repair factor composite bone supporting material prepared by the preparation method.
FIG. 8 is a scanning electron microscope image of the surface morphology of the bone supporting material prepared in example 1 of the present invention; the bone supporting material prepared in example 1 was immersed in 20mL of the simulated body fluid, maintained in a 37 ℃ water bath environment, replaced with the simulated body fluid for 24 hours each, taken out after 28 days, washed with deionized water, dried at low temperature, and observed for the surface morphology of each group of samples under SEM, and fig. 9 is a scanning electron microscope image of the bone supporting material prepared in example 1 of the present invention after mineralization in the simulated body fluid for 28 days.
Example 2
The preparation method of the repair factor composite bone supporting material specifically comprises the following steps:
S1, selecting a disc-shaped medical titanium alloy with the diameter of 12.0mm and the thickness of 0.3mm, sequentially polishing samples by using silicon sand paper with the model of 800 meshes, 1000 meshes, 1500 meshes and 2000 meshes, soaking the samples in a sodium hydroxide solution with the concentration of 1.4mol/L at 55 ℃ for 22 hours, sequentially carrying out ultrasonic vibration cleaning by using ethanol, acetone and deionized water for 35 minutes, and drying for later use;
S2, dissolving 22.5mgKGN into 1.5mL of acetone to obtain KGN solution; 2.5g of polylactic acid is dissolved in 10mL of mixed solvent of acetone and N, N-dimethylformamide with the volume ratio of 6:1 to obtain polylactic acid solution; mixing 1.5mLKGN of solution and 10mL of polylactic acid solution to obtain spinning solution for standby;
S3, applying an external voltage of 15kv and a propulsion rate of 1.4mL/h to the spinning solution obtained in the step S2 through an electrostatic spinning process, forming jet flow under the action of an external electric field, receiving the jet flow by utilizing the titanium alloy treated in the step S1, wherein the distance between a nozzle of an injector and the titanium alloy is 15cm, the rotating speed of a roller is 2000rpm, and the time is 5min, so that the jet flow is finally solidified into nano fibers on the surface of the titanium alloy, and the titanium alloy loaded with polylactic acid and KGN composite fibers is obtained for standby;
s4, adding 22g of natural silk cocoons into 1L of sodium carbonate aqueous solution with the concentration of 0.05mol/L, boiling for 25min at the temperature of 100 ℃, flushing with cold water, repeating the same treatment for 2 times, drying to obtain degummed silk, adding 100mL of lithium bromide aqueous solution with the concentration of 9.2mol/L into 22g of degummed silk, dissolving for 1.5h at the temperature of 70 ℃, dialyzing for 12h to obtain a silk fibroin solution, adding 6mL of glycidyl methacrylate, stirring for 4h, dialyzing for 24h to obtain a methacrylate modified silk fibroin solution for later use;
S5, mixing 25g of the titanium alloy treated in the S3 with 25g of modified mesoporous silica, adding a zinc nitrate hexahydrate solution with the concentration of 0.5mol/L for soaking treatment, standing at room temperature for 24 hours, freeze-drying, adding a methacrylate modified silk fibroin solution obtained by 100mLS4, uniformly stirring at 4 ℃, and freeze-drying at-2 ℃ to obtain a pretreated bone supporting material for later use;
S6, dissolving 200mg of oxidized icariin in 100mL of ethanol water solution with the mass fraction of 55% to obtain oxidized icariin solution, soaking the pretreated bone supporting material obtained in the S5 in the oxidized icariin solution, reacting for 22 hours at the temperature of 4 ℃, washing with deionized water, and freeze-drying to obtain the repair factor composite bone supporting material.
The preparation methods of the modified mesoporous silica and oxidized icariin were carried out with reference to example 1.
The invention provides a repair factor composite bone supporting material prepared by the preparation method.
Example 3
The preparation method of the repair factor composite bone supporting material specifically comprises the following steps:
s1, selecting a rod-shaped medical titanium alloy with the diameter of 3.0mm and the thickness of 10.0mm, sequentially polishing samples by using silicon sand paper with the model of 800 meshes, 1000 meshes, 1500 meshes and 2000 meshes, soaking the samples in a sodium hydroxide solution with the concentration of 1.8mol/L for 24 hours at the temperature of 60 ℃, sequentially carrying out ultrasonic vibration cleaning by using ethanol, acetone and deionized water for 40 minutes, and drying for later use;
S2, dissolving 40mgKGN in 2mL of acetone to obtain KGN solution; 3.0g of polylactic acid is dissolved in 10mL of mixed solvent of acetone and N, N-dimethylformamide with the volume ratio of 6:1 to obtain polylactic acid solution; mixing 2mLKGN solution and 10mL polylactic acid solution to obtain spinning solution for standby;
s3, applying external voltage 20kv to the spinning solution obtained in the step S2 through an electrostatic spinning process, wherein the propulsion rate is 1.6mL/h, so that the spinning solution forms jet flow under the action of an external electric field, receiving the jet flow by utilizing the titanium alloy treated in the step S1, wherein the distance between a nozzle of an injector and the titanium alloy is 15cm, the rotating speed of a roller is 3000rpm, and the time is 6min, and finally solidifying the jet flow on the surface of the titanium alloy into nano fibers to obtain the titanium alloy loaded with polylactic acid and KGN composite fibers for later use;
S4, adding 24g of natural silk cocoons into 1L of sodium carbonate aqueous solution with the concentration of 0.05mol/L, boiling for 30min at the temperature of 100 ℃, flushing with cold water, repeating the same treatment for 3 times, drying to obtain degummed silk, adding 100mL of lithium bromide aqueous solution with the concentration of 9.2mol/L into 24g of degummed silk, dissolving at the temperature of 75 ℃ for 2h, dialyzing for 12h to obtain a silk fibroin solution, adding 7mL of glycidyl methacrylate, stirring for 5h, dialyzing for 24h to obtain a methacrylate modified silk fibroin solution for later use;
S5, mixing 30g of the titanium alloy treated in the S3 with 35g of modified mesoporous silica, adding a zinc nitrate hexahydrate solution with the concentration of 0.5mol/L for soaking treatment, standing at room temperature for 24 hours, freeze-drying, adding a methacrylate modified silk fibroin solution obtained by 100mLS4, uniformly stirring at 4 ℃, and freeze-drying at-2 ℃ to obtain a pretreated bone supporting material for later use;
S6, 300mg of oxidized icariin is dissolved in 100mL of ethanol water solution with the mass fraction of 60% to obtain oxidized icariin solution, the pretreated bone supporting material obtained in the S5 is soaked in the oxidized icariin solution, the reaction is carried out for 24 hours at the temperature of 4 ℃, deionized water is used for washing, and freeze drying is carried out to obtain the repair factor composite bone supporting material.
The preparation methods of the modified mesoporous silica and oxidized icariin were carried out with reference to example 1.
The invention provides a repair factor composite bone supporting material prepared by the preparation method.
Comparative example 1
This comparative example provides a repair factor composite bone supporting material and a method for preparing the same, which is different from example 1 only in that polylactic acid is not included, and the remaining components, component contents, and method for preparing the same are as in example 1.
Comparative example 2
This comparative example provides a repair factor composite bone supporting material and a method for preparing the same, which is different from example 1 only in that modified mesoporous silica is not included, and the rest of components, component contents, and method for preparing the same are the same as example 1.
Comparative example 3
This comparative example provides a repair factor composite bone supporting material and a method for preparing the same, which is different from example 1 only in that methacrylate modified silk fibroin is not included, and the rest components, component contents, and preparation method are the same as example 1.
Comparative example 4
This comparative example provides a repair factor composite bone supporting material and a preparation method thereof, which are different from example 1 only in that icariin is not subjected to oxidation treatment, and the remaining components, component contents, and preparation method are the same as example 1.
Comparative example 5
This comparative example provides a repair factor composite bone supporting material and a method for preparing the same, which is different from example 1 only in that the soaking treatment of a zinc nitrate hexahydrate solution is not included, and the remaining components, component contents, and preparation method are the same as example 1.
Performance testing and results analysis
Mechanical property test of bone supporting material:
the bone supporting materials prepared in examples 1 to 3 and comparative examples 1 to 4 were extruded into test bars having a diameter of 20mm×10mm×100 μm (length×width×thickness), and after the samples were completely molded, they were placed in a stretching apparatus to perform a stretching test at a stretching rate of 1.0mm/min with a stretching force of 50N until they were broken, and the tensile strength and elongation at break of each group of the bone supporting materials were calculated; after the bone supporting materials prepared in examples 1 to 3 and comparative examples 1 to 4 were made into test bars, they were placed on a platform of a universal mechanical tester, compressed along the long axis of the test bars at a speed of 0.5mm/min, and stopped when the compression was 10% deformed, and compressive strength and elastic modulus were calculated.
And (3) testing the corrosion resistance of the bone supporting material:
the three-electrode system of the Shanghai Chenhua CHI660E electrochemical workstation is adopted, the auxiliary electrode is a platinum electrode, the reference electrode is a saturated calomel electrode, the bone supporting materials prepared in the example 1 and the comparative examples 1 and 3 are used as research electrodes, and the corrosive liquid is 3% NaCl aqueous solution for corrosion resistance measurement.
Cell adhesion performance test of bone supporting material:
Selecting MC3T3-E1 mouse embryo osteoblasts as experimental cells, culturing the experimental cells by using a DMEM medium containing 10% fetal bovine serum and 1% penicillin/streptomycin, culturing the osteoblasts on the surfaces of the bone supporting materials prepared in examples 1-3 and comparative examples 1-4 respectively for 24 hours in a 96-well plate, taking out the bone supporting materials, and repeatedly washing the bone supporting materials with PBS buffer solution to remove cells which are not attached successfully; under the condition of avoiding light, 30 mu LCCK-8 solution and 300 mu L of culture medium are added into each hole, the culture is continued for 12 hours, 100 mu L of supernatant is sucked, and the absorbance (OD) is measured by an enzyme-labeling instrument, and the wavelength is set to 450nm. Cell adhesion was calculated according to the following formula: adhesion = (number of adhered cells/total number of cells) ×100%.
Antibacterial property test of bone supporting material:
The bone supporting materials prepared in examples 1-3 and comparative examples 4 and 5 were placed in respective groups on 48-well plates, 3 samples were taken in each group, the concentration of the E.coli bacteria solution was adjusted to 10 6 CFU/mL, then 300. Mu.L of E.coli bacteria solution was added to each well, and covered with a sterile PE film, and spread out to uniformly cover the surface of the sample, and to prevent volatilization of the bacteria solution on the surface of the sample, sterile water was added to the space around the 48-well plate, and a certain humidity was provided. After incubating for 6 hours in a 37 ℃ electrothermal constant temperature incubator, eluting bacteria on the surface of a sample by using PBS solution, collecting the bacteria, absorbing 100 mu L of elution liquid, dripping the elution liquid on a nutrient agar culture medium plate, uniformly spreading the elution liquid, incubating for 24 hours at the temperature of 37 ℃ upside down, taking out the plate, photographing and counting the number of living bacterial colonies in a full-automatic bacterial colony analyzer, and detecting the antibacterial performance of the bacterial colony.
Anti-inflammatory performance test of bone supporting material:
After the mouse macrophage-like cell line RAW264.7 cells were inoculated and cultured on the surfaces of the bone supporting materials prepared in examples 1 to 3 and comparative examples 3 and 4 and cultured for 3 days, the concentration of inflammatory factor TNF- α in the culture supernatant of the RAW264.7 cells was detected using a flow cytometer, thereby evaluating the anti-inflammatory effect of the bone supporting materials.
Bone supporting material repair factor release test:
Immersing the bone supporting material samples prepared in the example 1 and the comparative examples 3 and 4 in phosphate buffer, and preserving in 37 ℃; for a total of 40 days, supernatants were removed on days 1, 7, 14, 21, 28, 35, 42, respectively, and the concentration of the repair factor in the solution was measured using an ICP-MS apparatus.
Analysis of results
Fig. 1 is a graph showing the tensile strength and elongation at break test results of the bone supporting materials prepared in examples 1 to 3 and comparative examples 1 to 4, and fig. 2 is a graph showing the compressive strength and elastic modulus test results of the bone supporting materials prepared in examples 1 to 3 and comparative examples 1 to 4, wherein the tensile strength and compressive strength of the bone supporting materials prepared in comparative examples 1 to 4 are significantly lower than those of the bone supporting materials prepared in examples 1 to 3, and the tensile strength and compressive strength of comparative example 1 are the lowest, and the bone supporting materials prepared in comparative example 1 do not include polylactic acid, and only the KGN cartilage differentiation inducer is loaded on the surface of the titanium alloy, so that polylactic acid is added to be loaded on the surface of the titanium alloy in an electrospinning manner, thereby being beneficial to improving the mechanical properties of the titanium alloy; comparative example 2 does not include modified mesoporous silica, and also decreases mechanical properties; comparative example 3 does not include methacrylate modified silk fibroin, and the silk fibroin is taken as a natural high polymer material, has good mechanical properties, and shows that Schiff base reaction occurs between amino groups of the silk fibroin and aldehyde groups of oxidized icariin, so that the stability of gel on the surface of the titanium alloy is improved, and the mechanical properties of the bone supporting material are improved; in comparative example 4, icariin does not undergo oxidation treatment, and therefore, icariin does not contain aldehyde groups, cannot react with modified silk fibroin by Schiff base, cannot form a stable gel structure, and can be coated with titanium alloy to reduce mechanical properties.
Fig. 3 is a graph showing the corrosion resistance test results of the bone supporting materials prepared in the embodiment 1 and the comparative examples 1 and 3, as compared with the bone supporting materials prepared in the comparative examples 1 and 3, the self-corrosion current density of the bone supporting material prepared in the embodiment 1 is obviously reduced, the self-corrosion potential is obviously increased, which indicates that the orthopedic implant material prepared in the embodiment 1 has excellent corrosion resistance, the bone supporting material prepared in the embodiment 1 takes a metal titanium alloy as a base material, polylactic acid and KGN composite fiber are loaded on the surface in an electrostatic spinning manner, modified mesoporous silica obtained by carrying out surface activation treatment by a plasma immersion ion implantation technology is added, the modified mesoporous silica is soaked in an antibacterial active solution, a stable protective film is formed on the surface of the titanium alloy due to the existence of the modified silk fibroin, schiff base reaction occurs between amino groups of the modified silk fibroin and aldehyde groups of the oxidized icariin, and therefore the stable three-dimensional structure is formed, the titanium alloy is prevented from being directly contacted with bone matrix tissue to be corroded rapidly.
FIG. 4 is a graph showing the results of cell adhesion performance tests of the bone supporting materials prepared in examples 1 to 3 and comparative examples 1 to 4 according to the present invention, wherein the cell adhesion rates of the bone supporting materials prepared in examples 1 to 3 are 35.1%, 36.3% and 34.9%, respectively, and the cell adhesion rates of the bone supporting materials prepared in comparative examples 1 to 4 are only 27.5%, 24.3%, 22.8% and 29.4%, respectively; the bone supporting material prepared in comparative example 1 does not include polylactic acid, and cannot provide more surface area for adhesion of bone cells, so that the cell adhesion rate is reduced; the reason why the modified mesoporous silica is not included in comparative example 2 and the cell adhesion rate is reduced is that the addition of the modified mesoporous silica helps to increase the specific surface area of the titanium alloy, improve the roughness and the porosity thereof, provide more bioactive sites for the titanium alloy and promote the adsorption and proliferation of bone cells; comparative example 3 does not include modified silk fibroin, does not introduce double bonds, lacks the presence of an adhesive group, reduces migration and proliferation of bone cells, thereby slowing down bone tissue repair and regeneration processes; icariin in comparative example 4 was not subjected to oxidation treatment, and could not interact with modified silk fibroin to form an adhesive gel structure, thereby reducing its adhesive property.
FIG. 5 is a graph showing the results of antibacterial property tests of the bone supporting materials prepared in examples 1 to 3 and comparative examples 4 and 5 according to the present invention, wherein the antibacterial rates of the bone supporting materials prepared in examples 1 to 3 are 87.3%, 86.5% and 88.1%, respectively, and the antibacterial rates of the bone supporting materials prepared in comparative examples 4 and 5 are 79.6% and 67.8%, respectively; icariin in comparative example 4 was not subjected to oxidation treatment, but icariin was used as an active ingredient of a Chinese medicinal material icariin, and an oxidized icariin obtained by carrying out hydroformylation modification on the C-3 position had an antibacterial activity, so that the antibacterial performance thereof was lowered; comparative example 5 does not include a zinc nitrate hexahydrate solution, and zinc ions are released into the surrounding environment, combined with phospholipids and proteins on the bacterial cell membrane, destroying the integrity of the cell membrane, causing leakage of intracellular material, causing bacterial death or growth limitation, thereby reducing the risk of infection, and since comparative example 5 does not introduce zinc ions, the antibacterial properties of the bone supporting material are greatly reduced.
FIG. 6 is a graph showing the results of anti-inflammatory properties of the bone supporting materials prepared in examples 1 to 3 and comparative examples 3 and 4, wherein the TNF- α concentrations in the examples 1 to 3 are 218.5pg/mL, 209.8pg/mL and 224.6pg/mL, respectively, and the TNF- α concentrations in the comparative examples 3 and 4 are as high as 262.4pg/mL and 298.6pg/mL, respectively, and the cells cultured on the surface of the bone supporting material prepared in examples 1 to 3 release less inflammatory factors, indicating that the bone supporting materials prepared in examples 1 to 3 have good anti-inflammatory properties, and the silk fibroin and oxidized icariine act synergistically to provide anti-inflammatory effects to the bone supporting material.
FIG. 7 is a graph showing the results of the test for releasing the repair factor from the bone supporting materials prepared in example 1 and comparative examples 3 and 4, wherein the release rate of the repair factor from the bone supporting material prepared in example 1 is relatively slow, and the release rate of the repair factor from the bone supporting material prepared in example 1 reaches 0.68ng/mL after 42 days, and the release rate of the repair factor from the bone supporting material prepared in comparative examples 3 and 4 is relatively fast, as compared with the release rate of the repair factor from the bone supporting material prepared in example 1, and the release rate of the repair factor from the bone supporting material prepared in comparative examples 3 and 4 reaches 0.79ng/mL and 0.85ng/mL after 42 days, respectively; the explanation shows that the silk fibroin and oxidized icariin obtained by adding glycidyl methacrylate into the titanium alloy undergo Schiff base reaction between amino groups of the silk fibroin and aldehyde groups of the oxidized icariin to form a three-dimensional porous crosslinked hydrogel structure, which is beneficial to slow and orderly release of repair factors.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made hereto without departing from the spirit and principles of the present invention.
The invention and its embodiments have been described above with no limitation, and the invention is illustrated in the figures of the accompanying drawings as one of its embodiments, without limitation in practice. In summary, those skilled in the art, having benefit of this disclosure, will appreciate that the invention can be practiced without the specific details disclosed herein.
Claims (9)
1. A preparation method of a repair factor composite bone supporting material is characterized by comprising the following steps: the preparation method comprises the following steps:
S1, selecting medical titanium alloy, extruding and forming to obtain a titanium plate or bar, sequentially polishing samples by using silicon sand paper with the model of 800 meshes, 1000 meshes, 1500 meshes and 2000 meshes, soaking the samples in 1.0-1.8mol/L sodium hydroxide solution for 20-24 hours at 50-60 ℃, sequentially carrying out ultrasonic vibration cleaning by using ethanol, acetone and deionized water for 30-40 minutes, and drying for later use;
S2, dissolving KGN in acetone to obtain KGN solution; dissolving polylactic acid in a mixed solvent of acetone and N, N-dimethylformamide in a volume ratio of 6:1 to obtain a polylactic acid solution; mixing KGN solution and polylactic acid solution to obtain spinning solution for standby;
S3, applying external voltage to the spinning solution obtained in the step S2 through an electrostatic spinning process to form jet flow under the action of an external electric field, and receiving the jet flow by utilizing the titanium alloy treated in the step S1 to finally solidify the jet flow into nano fibers on the surface of the titanium alloy to obtain the titanium alloy loaded with polylactic acid and KGN composite fibers for later use;
S4, adding natural cocoons into a sodium carbonate aqueous solution with the concentration of 0.05mol/L, boiling for 20-30min at the temperature of 100 ℃, washing with cold water, repeating the same treatment for 2-3 times, drying to obtain degummed silk, adding a lithium bromide aqueous solution with the concentration of 9.2mol/L, dissolving for 1-2h at the temperature of 65-75 ℃, dialyzing for 12h to obtain a silk fibroin solution, adding glycidyl methacrylate, stirring for 3-5h, dialyzing for 24h to obtain a methacrylate modified silk fibroin solution for later use;
s5, mixing the titanium alloy treated in the step S3 with modified mesoporous silica, adding a zinc nitrate hexahydrate solution with the concentration of 0.5mol/L for soaking treatment, standing at room temperature for 24 hours, freeze-drying, adding the methacrylate modified silk fibroin solution obtained in the step S4, uniformly stirring at 4 ℃, and freeze-drying at-2 ℃ to obtain a pretreated bone supporting material for later use;
The modified mesoporous silica is obtained by performing surface activation treatment on mesoporous silica by a plasma immersion ion implantation technology, and the treatment conditions are as follows: argon is injected into the mesoporous silica by adopting a GPI-100 gas injector, the argon flow is 20-40sccm, the radio frequency is 8000-10000W, the pulse voltage is-20 to-15 kV, the working pressure is 1X 10 -2-10×10-2 Pa, the pulse width is 80-120 mu s, the pulse frequency is 40-60Hz, and the treatment time is 8-10min;
S6, dissolving oxidized icariin in an ethanol water solution with the mass fraction of 50-60% to obtain an oxidized icariin solution with the concentration of 0.5-3mg/mL, soaking the pretreated bone supporting material obtained in the S5 in the oxidized icariin solution, reacting for 20-24 hours at the temperature of 4 ℃, washing with deionized water, and freeze-drying to obtain the repair factor composite bone supporting material.
2. The method for preparing a repair factor composite bone supporting material according to claim 1, wherein: in S2, the addition amount of KGN in acetone is 0.01-0.02g/mL; the addition amount of the polylactic acid in the mixed solvent of the acetone and the N, N-dimethylformamide is 0.2-0.3g/mL; the volume ratio of the KGN solution to the polylactic acid solution is 1-2:10.
3. The method for preparing a repair factor composite bone supporting material according to claim 2, wherein: in S3, conditions of the electrospinning process: the external voltage is 10-20kv, the propulsion rate is 1.2-1.6mL/h, the distance between the injector nozzle and the titanium alloy is 15cm, the rotating speed of the roller is 1000-3000rpm, and the time is 4-6min; the total weight of the polylactic acid and KGN composite fiber accounts for 1-2% of the total dry weight of the bone supporting material.
4. A method for preparing a repair factor composite bone supporting material according to claim 3, wherein: in S4, the addition amount of the natural silkworm cocoons in the sodium carbonate aqueous solution is 20-24g/L; the addition amount of the degummed silk in the lithium bromide aqueous solution is 0.2-0.24g/mL; the mass volume ratio of the degummed silk to the glycidyl methacrylate is 20-24g:5-7mL.
5. The method for preparing the repair factor composite bone supporting material according to claim 4, wherein: in S5, the mass-volume ratio of the titanium alloy to the modified mesoporous silica to the methacrylate modified silk fibroin solution is 20-30g:15-35g:100mL.
6. The method for preparing a repair factor composite bone supporting material according to claim 5, wherein: in S6, the preparation method of the oxidized icariin specifically comprises the following steps:
dissolving icariin in absolute ethyl alcohol to obtain an icariin solution; dissolving sodium periodate in distilled water to obtain sodium periodate aqueous solution, mixing icariine solution and sodium periodate aqueous solution, reacting for 3-5h under the condition of light-proof ice bath, centrifuging for 20-30min at 2000-3000rpm, dialyzing for 68-74h with dialysis bag with molecular weight cut-off of 14kD, and lyophilizing the dialysate to obtain oxidized icariine.
7. The method for preparing a repair factor composite bone supporting material according to claim 6, wherein: the addition amount of icariin in absolute ethyl alcohol is 0.2-0.25g/mL; the mass volume ratio of the sodium periodate to the distilled water is 0.12-0.16g/mL.
8. The method for preparing a repair factor composite bone supporting material according to claim 7, wherein:
the medical titanium alloy comprises the following components in percentage by mass: zn:2.5-4%, ca:1.2-2.1%, sr:0.12-0.24%, al:0.05-0.08%, and the balance being titanium.
9. A repair factor composite bone supporting material, characterized in that: the bone supporting material is prepared by the preparation method of any one of claims 1 to 8.
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