High-strength absorbable composite active internal fixation device and preparation method thereof

Abstract

The present application relates to a high-strength absorbable composite active internal fixation device and a preparation method thereof. Specifically, the present application discloses the internal fixation device and a preparation method thereof, and the internal fixation device has excellent biological activity and mechanical properties.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biomedical devices, in particular to a high-strength absorbable composite active internal fixation device and a preparation method thereof. BACKGROUND

[0002] Bone injury is a high incidence disease in clinic, and internal fixation is the most common treatment. Traditional metal internal fixation materials must be removed by secondary surgery after healing, which increases the pain and economic burden of patients. Biodegradable materials have become the development trend to replace traditional non-absorbable materials. Although there are products on the market, their poor mechanical properties and inflammatory reactions often lead to implant failure.

[0003] Polylactic acid is a biodegradable polymer material that is safe to the human body and friendly to the environment. It can be used to make medical sutures, microcapsules for injection, degradable bone nails, implants, artificial bones, artificial skin, etc. Its characteristic is that the metabolic product is non-toxic and is ultimately converted into carbon dioxide and water in the body.

[0004] Existing absorbable internal fixation implant products represented by polylactic acid generally have low strength and are prone to brittle fracture, which is the main reason for implant failure. The mechanical attenuation of the material caused by the processing process is a difficult problem that has not been solved so far. SUMMARY

[0005] The purpose of the present application is to provide an internal fixation device with excellent biological activity and mechanical properties and a preparation method thereof.

[0006] In a first aspect of the present application, a preparation method of an internal fixation device is provided, comprising the steps of:

[0007] 1) providing a first mixture, wherein the first mixture comprises bioactive nanoparticles, a catalyst and a biomedical grade monomer;

[0008] 2) allowing the first mixture to undergo a polymerization reaction to obtain a first polymer;

[0009] 3) granulating the first polymer;

[0010] 4) injecting the granulation product into an injection molding machine to form a first blank by injection molding;

[0011] 5) annealing the first blank to obtain a second blank;

[0012] 6) extruding the second blank to form the internal fixation device, and precisely processing the obtained product to obtain the internal fixation device.

[0013] In another preferred embodiment, the bioactive nanoparticles are inorganic particles selected from the group consisting of hydroxyapatite, tricalcium phosphate, calcium sulfate, calcium phosphate, magnesium sulfate, or a combination thereof.

[0014] In another preferred embodiment, the inorganic particles are surface-modified inorganic particles, and the surface modification is a modification treatment by a modifying substance selected from the group consisting of a silane coupling agent, a polylactic acid (e.g., a low-molecular-weight polylactic acid), a polylactic acid-polycaprolactone copolymer, or a combination thereof.

[0015] In another preferred embodiment, the inorganic particles have a particle size of 5-30,000 nm, preferably 10-25,000 nm, preferably 20-20,000 nm, preferably 30-500 nm, preferably 40-400 nm, more preferably 50-350 nm.

[0016] In another preferred embodiment, the surface-modified inorganic particles have a mass content of the modifying substance of 0.001-40 wt%, preferably 0.01-20 wt%, more preferably 0.015-20 wt%.

[0017] In another preferred embodiment, the catalyst is selected from the group consisting of zinc oxide, stannous octoate, stannous chloride, butyl magnesium, or a combination thereof.

[0018] In another preferred embodiment, the biomedically pure monomer is selected from the group consisting of L-lactide, D-lactide, rac-lactide, trimethylene carbonate, caprolactone, glycolide, or a combination thereof.

[0019] In another preferred embodiment, the first mixture has a mass content of the biologically active nanoparticles of 0.001-80 wt%, preferably 0.01-60 wt%, more preferably 0.01-40 wt%.

[0020] In another preferred embodiment, the first mixture has a mass content of the catalyst of 0.01-1.00 wt%, preferably 0.03-0.80 wt%, more preferably 0.04-0.60 wt%.

[0021] In another preferred embodiment, the first mixture has a mass content of the biomedically pure monomer of 20-99.999 wt%, preferably 40-99.99 wt%, more preferably 60-99.99 wt%.

[0022] In another preferred embodiment, the first polymer has a number average molecular weight of 50-1000 kDa, preferably 80-800 kDa, more preferably 100-600 kDa.

[0023] In another preferred embodiment, the first polymer is selected from the group consisting of an L-polylactic acid homopolymer, a rac-polylactic acid homopolymer, a rac-lactide-caprolactone copolymer, an L-lactide-glycolide copolymer.

[0024] In another preferred embodiment, the pelletizing has one or more features selected from the group consisting of:

[0025] 1) the pelletizing is performed using a single screw or a twin screw;

[0026] 2) the temperature of the pelletizing is 40-300°C, preferably 60-260°C, more preferably 100-240°C;

[0027] 3) the rotation speed of the single screw or the twin screw is 20-60 rpm, preferably 30-50 rpm, more preferably 35-45 rpm.

[0028] In another preferred embodiment, the injection molding has one or more features selected from the group consisting of:

[0029] 1) the temperature of the injection molding machine barrel is 50-250°C, preferably 80-220°C, more preferably 120-200°C;

[0030] 2) the temperature of the mold is 10-150°C, preferably 15-120°C, more preferably 20-80°C;

[0031] 3) the injection molding time is 2-30 s, preferably 3-25 s;

[0032] 4) the injection molding pressure is 0.2-20 MPa, preferably 1-15 MPa;

[0033] 5) the dwell time is 5-100 s, preferably 10-60 s;

[0034] 6) the dwell pressure is 1-20 MPa, preferably 3-15 MPa.

[0035] In another preferred embodiment, the annealing process has one or more features selected from the group consisting of:

[0036] 1) the annealing process is performed with the first blank and the mold together;

[0037] 2) the cooling rate of the annealing process is 5-50°C / min, preferably 10-40°C / min;

[0038] 3) the cooling time of the annealing process is 4-15 min, preferably 5-10 min.

[0039] In another preferred embodiment, the extrusion molding has one or more features selected from the group consisting of:

[0040] 1) the extrusion temperature of the extrusion molding is 60-200°C, preferably 80-180°C, more preferably 100-160°C;

[0041] 2) the extrusion pressure of the extrusion forming is 50N-100kN, preferably 100N-50kN.

[0042] In another preferred embodiment, in step 6), the extrusion forming is repeated.

[0043] In another preferred embodiment, the number of repetitions is 2-10 times, preferably 3-6 times.

[0044] In a second aspect of the present application, there is provided an internal fixation device, which is prepared by the method of the first aspect of the present application.

[0045] In another preferred embodiment, the internal fixation device has one or more features selected from the group consisting of:

[0046] 1) the bending strength of the internal fixation device is 100-300MPa, preferably 150-300MPa, more preferably 250-300MPa;

[0047] 2) the bending modulus of the internal fixation device is 2.5-5GPa, preferably 3-4GPa.

[0048] In another preferred embodiment, the material forming the internal fixation device is selected from the group consisting of: poly-L-lactic acid, poly-DL-lactic acid, poly-DL-lactide-co-caprolactone, poly-L-lactide-co-glycolide.

[0049] In another preferred embodiment, the internal fixation device is selected from the group consisting of: internal fixation compression screw, interface screw, rib rod, internal fixation plate.

[0050] It should be understood that, within the scope of the present application, each of the above technical features of the present application and the technical features specifically described hereinafter (such as the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0051] Figure 1 is a picture of the internal fixation rod obtained in Example 1.

[0052] Figure 2 is the mechanical test result of the internal fixation device.

[0053] Figure 3 is the ALP staining result of Example 3.

[0054] Figure 4 is the quantitative analysis result of the ALP staining of Example 3.

[0055] Figure 5 is a picture of the internal fixation screw in Example 1 and the injection molded screw in Comparative Example 1.

[0056] Figure 6 Table 1 is the mechanical comparison result of the screw obtained in Example 1 and the injection molded screw in Comparative Example 1. DETAILED DESCRIPTION

[0057] The present inventors have made a long-term and in-depth research, and unexpectedly prepared an internal fixation device with excellent biological activity and mechanical properties by improving the preparation process. On this basis, the present inventors completed the present application.

[0058] Internal fixation device

[0059] The present application develops active nanoparticle composite technology, low-damage injection molding combined with cold extrusion secondary orientation and crystallization-induced self-reinforcement technology, thereby significantly improving the biological activity and mechanical strength of the implanted material, reducing the reduction rate of the mechanical properties of the implanted device in the early stage, weakening the inflammatory reaction, and improving the safety and effectiveness of the absorbable internal fixation product for the user.

[0060] The biological activity includes but is not limited to cell adhesion promoting ability, osteoinduction, and bone conduction.

[0061] The internal fixation device has in vivo degradation and absorption functions, and has bone induction activity.

[0062] The biological activity of the internal fixation device is that the material has good bone conduction and osteogenic regeneration induction ability, and can promote in situ regeneration of bone tissue.

[0063] Preparation method

[0064] The present application provides a preparation method of the internal fixation device, comprising the following steps:

[0065] 1) In-situ induced polymerization of bioactive nanoparticles and bio-medical grade monomers;

[0066] 2) After the medical grade polylactic acid-based polymer obtained by polymerization is collected after impurity removal, a blank is prepared by non-destructive processing;

[0067] 3) The blank is processed into a profile material by self-reinforcement technology;

[0068] 4) The profile material is precisely processed to prepare an organic-inorganic composite high-strength absorbable internal fixation device.

[0069] Preferably, the bio-medical grade monomers include but are not limited to L-lactide, D-lactide, racemic lactide, trimethylene carbonate, caprolactone, glycolide or a mixture of the above monomers;

[0070] Preferably, the number average molecular weight of the polylactic acid-based polymer is 100-600 kDa, and the components include, but are not limited to, poly-L-lactic acid, poly-D-lactic acid, poly-L-lactic acid-co-caprolactone (mass ratio of comonomer 5:95-95:5), poly-D-lactic acid-co-caprolactone (mass ratio of comonomer 5:95-95:5), or a blend of the above polymers;

[0071] Preferably, the main component of the bioactive nanoparticles is an inorganic particle, which acts as a nucleating agent during polymer crystallization, refines the grain, and is selected from one or a mixture of hydroxyapatite, tricalcium phosphate, calcium sulfate, calcium phosphate, and magnesium sulfate;

[0072] Preferably, the bioactive nanoparticles are surface-modified, which can induce polymerization of bio-medical grade monomers at the interface between the particles and the monomers, improve the dispersion of the nanoparticles, and retain the biological activity of the particles themselves.

[0073] Preferably, the non-destructive processing step includes single-screw or twin-screw extrusion granulation, injection molding, and annealing process. The single-screw or twin-screw temperature during granulation is 40-200°C, the barrel temperature during injection molding is 50-250°C, the mold temperature is 20-150°C, the injection pressure is 1-20 MPa, the injection time is 2-20 s, the holding time is 50-100 s, the annealing cooling rate is 5-50°C / min, and the cooling time is 5-10 min.

[0074] Preferably, the self-reinforcing technology is cold extrusion technology, with an extrusion temperature of 60-200°C and an extrusion pressure of 100 N-100 kN, and the ratio of the cross-sectional areas before and after extrusion is 1-100.

[0075] Further, the multi-stage self-reinforcing method is to form a profile by extrusion strengthening of the embryo material, and then to perform multiple extrusions on the profile and cut off the appropriate size.

[0076] Specifically, the method comprises the following steps:

[0077] 1) Synthesis The polymerization monomers, catalyst, and modified bioactive nanoparticles are weighed and added to the reactor in a glove box, sealed, taken out, heated to 130-150°C using an oil bath, and reacted for 6 h under inert gas protection. The polymer is collected using dichloromethane and anhydrous ethanol, and dried.

[0078] 2) Granulation Single-screw or twin-screw granulation is used, with a temperature of 130-190°C and a screw rotation speed of 4-80 rpm.

[0079] 3) Injection moldingThe granules are added into a barrel, the barrel temperature is 50-250℃, the mold temperature is 20-150℃, the injection pressure is 1-20MPa, the injection time is 2-20s, and the pressure maintaining time is 5-50s;

[0080] 4) Annealing The blank is annealed together with the mold, the cooling rate is 5-50℃ / min, and the cooling time is 5-10min;

[0081] 5) Cold extrusion The blank obtained in 4) is added into an extrusion barrel, and the blank is extruded into a certain compression ratio by extrusion under a temperature lower than the melting temperature;

[0082] 6) Shaping The profile is precisely processed to obtain the absorbable internal fixation device with a specific shape.

[0083] The degradable high polymer accounts for 20-99.999wt% of the composite, and the inorganic particles account for 0.001-80wt% based on the total weight of the degradable high polymer and the inorganic particles.

[0084] The degradable high polymer includes but is not limited to poly-L-lactic acid, poly-D-lactic acid, poly-L-lactic acid and caprolactone copolymer (mass ratio of comonomer 5:95~95:5), poly-D-lactic acid and caprolactone copolymer (mass ratio of comonomer 5:95~95:5) or a blend of the above polymers.

[0085] The bioactive nanoparticles are inorganic particles, which play a role of nucleating agent in the polymer crystallization process, refine the grain, and the composition is selected from one or a mixture of hydroxyapatite, tricalcium phosphate, calcium sulfate, calcium phosphate, magnesium sulfate, and the particle size is 10-800nm.

[0086] The non-destructive processing step includes single-screw or double-screw extrusion granulation, injection molding and annealing process, the single-screw or double-screw temperature in the granulation process is 40-200℃, the barrel temperature in the injection molding process is 50-250℃, the mold temperature is 20-150℃, the injection pressure is 1-20MPa, the injection time is 2-20s, the pressure maintaining time is 50-100s, the annealing cooling rate is 5-50℃ / min, and the cooling time is 5-10min.

[0087] The self-reinforcing technology is a cold extrusion technology, the extrusion temperature is 60-200℃, the extrusion pressure is 100N-100kN, and the ratio of the cross-sectional area before and after extrusion is 1-100, and the extrusion mold used in the application is designed according to the shape of the prepared internal fixation device.

[0088] Compared with the prior art, the application has the following main advantages:

[0089] (1) In the processing process, the orientation of the high molecular chain is strengthened due to the existence of the orientation force field, and the crystal region directional growth is enhanced in the crystallization strengthening process, thereby improving the comprehensive mechanical properties of the material;

[0090] (2) The calcium and phosphorus-based nanoparticles with bone inductive activity are added, the dispersion of the nanoparticles is improved by using the in-situ polymerization method, the biological activity of the composite material is enhanced, the inflammatory reaction in the degradation process is reduced, the crystal grains are refined, and the mechanical properties of the material are enhanced;

[0091] (3) The machining is further processed according to the material use, so as to adapt to different bone quality and fracture surface fixation, thereby expanding the use range of the material;

[0092] (4) The internal fixation device has excellent biological activity and mechanical properties, has biological fixation effect, and has bone repair induction and regeneration function.

[0093] The application will be further described below in combination with specific examples. It should be understood that these examples are only used to illustrate the application and are not used to limit the scope of the application. The experimental methods in the following examples are not specified, and the general conditions or the conditions recommended by the manufacturer are usually used. Unless otherwise specified, percentages and parts are calculated by weight.

[0094] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as familiar to those skilled in the art. In addition, any method and material similar or equivalent to those described can be applied to the method of the application. The preferred implementation methods and materials described herein are only used for demonstration.

[0095] Raw materials

[0096]

[0097] General test method

[0098] Mechanical properties

[0099] According to GB / T 9341-2008, the bending performance of the material is tested by three-point bending method using a mechanical testing machine (CMT-2503, MTS). The material is made into a rod with a diameter of 6 mm, each sample is 40 mm long, the span is 20 mm, the experimental rate is 1 mm / min, and the test temperature is 25℃.

[0100] According to ASTM F543-2013, the torsional performance of the device is measured using a small load torsional test system (55MT, Instron). The final device is used as a sample, the loading speed is 1 rad / min, and the test temperature is 25℃.

[0101] Biological activity

[0102] The obtained composite was hot-pressed by a flat press at 180°C to form a film with a thickness of 0.2 mm. The in vitro cytocompatibility of the composite material was evaluated by MTT method using rBMSCs as model cells. The morphology and adhesion of rBMSCs on the composite film were observed by SEM. The osteogenic differentiation ability of rBMSCs on the composite film was evaluated by ALP staining and ALP activity experiment. The above experiments were all performed using pure polylactic acid film as a control sample.

[0103] Preparation of internal fixation device in Example 1

[0104] 1) Synthesis: L-lactide, stannous octoate, and modified hydroxyapatite (average particle size 50 nm) were weighed into a reactor in a glove box, sealed, and taken out. An oil bath was used to heat to 135°C, and the reaction was carried out under inert gas protection for 6 hours. The polymer was collected using dichloromethane and anhydrous ethanol, and dried.

[0105] 2) Granulation: single-screw granulation was used at a temperature of 200°C and a screw speed of 40 rpm.

[0106] 3) Injection molding: the granules were added to a hopper with a temperature of 170°C, and the mold temperature was 30°C. The injection pressure was 10 MPa, the injection time was 3 s, the holding pressure was 8 MPa, and the holding time was 10 s.

[0107] 4) Annealing: the blank was annealed together with the mold at a cooling rate of 30°C / min and a cooling time of 5 min.

[0108] 5) Cold extrusion: the blank obtained in 4) was added to an extrusion hopper, and the blank was extruded into a certain compression ratio by extrusion at 160°C with an extrusion pressure of 100 N.

[0109] 6) Molding: the profile was machined to obtain an absorbable internal fixation device.

[0110] The picture of the obtained internal fixation device is shown in Figure 1 .

[0111] The mass fraction of L-lactide in the device was 99.88wt%, the mass fraction of the catalyst stannous octoate was 0.11wt%, and the mass fraction of modified hydroxyapatite was 0.01wt%.

[0112] The difference in torsional properties between the reinforced internal fixation screw and the pure polylactic acid injection internal fixation device is shown in Figure 6 ​​​​​​​​​​​​The screw prepared by using the above-mentioned reinforcing method has a peak torque of 55.11 N·mm, a peak angle of 115.5°, and a bending strength of 225 MPa. Compared with the screw obtained by direct injection molding, the peak torque of the cutting screw is increased by 87%, the peak angle is increased by 115%, and the bending strength is increased by 3.13 times. The reinforced device is more robust than the injection molding.

[0113] Mechanical property determination of internal fixation device in Example 2

[0114] The rod obtained by cold extrusion in 5) of Example 1 was taken out and the bending property of the material was tested by a three-point bending method. Each sample was 40 mm long, with a span of 20 mm, an experimental rate of 1 mm / min, and a test temperature of 25°C. The reference sample was a rod obtained by melt extrusion after granulation of the same raw material in 2), and the data are shown in Table 1. Figure 2 The bending strength of the extrusion-reinforced rod was 224.74 MPa, and the bending modulus was 3.5 GPa, while the bending strength of the non-reinforced rod was 54.48 MPa, and the bending modulus was 1.45 GPa. Using the reinforcing method described in the present patent, the bending strength can be increased by 3.13 times, and the bending modulus can be increased by 1.41 times.

[0115] Biological activity of internal fixation device in Example 3

[0116] 1) Synthesis: racemic lactide, stannous octoate, and modified hydroxyapatite (average particle size 100 nm) were weighed into a reactor in a glove box, sealed, and taken out. An oil bath was used to heat to 135°C, and the reaction was carried out under inert gas protection for 6 hours. The polymer was collected using dichloromethane and anhydrous ethanol, and dried;

[0117] 2) Granulation: a single-screw granulator was used at a temperature of 190°C and a screw speed of 36 rpm;

[0118] 3) Injection molding: the granules were added to the hopper, the hopper temperature was 170°C, the mold temperature was 40°C, the injection pressure was 10 MPa, the injection time was 3 s, the holding pressure was 8 MPa, and the holding time was 10 s;

[0119] 4) Annealing: the blank was annealed together with the mold, the cooling rate was 20°C / min, and the cooling time was 8 min;

[0120] 5) Cold extrusion: the blank obtained in 4) was added to the extrusion hopper, and the blank was extruded into a certain compression ratio by extrusion at 140°C, with an extrusion pressure of 500 N;

[0121] 6) Molding: the profile was machined by turning to obtain an absorbable internal fixation device.

[0122] The mass fraction of racemic lactide is 99.79wt%, the mass fraction of modified hydroxyapatite (SHA) is 0.10wt%, and the mass fraction of catalyst is 0.11wt%.

[0123] The obtained composite is hot-pressed into a film with a thickness of 0.2mm by using a flat plate vulcanizing machine at 180℃, and the ALP staining and ALP activity experiment are used to evaluate the osteogenic differentiation ability of rat rBMSCs cells on the composite film. The results are shown in Figure 3 , Figure 4 .

[0124] Figure 3 The ALP staining of rBMSCs co-cultured with racemic polylactic acid (PDLLA) film and racemic polylactic acid-modified hydroxyapatite composite (PDLLA-SHA_X) film for 7d and 14d is shown in the figure. It can be seen that the ALP expression intensity of the rBMSCs cells in the PDLLA-SHA_0.1 experimental group at each time point is better than that in the other experimental groups, indicating that it has the best ability to promote the osteogenic differentiation of rBMSCs.

[0125] Figure 4 The quantitative analysis of the ALP activity of rat mesenchymal stem cells on the polymer film at 7d and 14d is shown in the figure. At 7d of cell and material co-culture, there is no significant difference between pure PDLLA and PDLLA-SHA_0.02, PDLLA-SHA_0.05 and PDLLA-SHA_0.1 modified films, and PDLLA-SHA_0.1 shows better alkaline phosphatase expression than the other three groups. At 14d of co-culture, PDLLA-SHA_0.02, PDLLA-SHA_0.05 and PDLLA-SHA_0.1 groups and pure PDLLA group show obvious difference, and the ALP activity of PDLLA-SHA_0.1 group is still better than the other three experimental groups. The results are consistent with the ALP staining. The above experiments show that the more SHA is introduced, the highest ALP activity of the cells on the composite film. This is mainly because HA, as the main mineral component of natural bone, has excellent bone binding and bone conduction ability.

[0126] Preparation of internal fixation device C1 in Comparative Example 1

[0127] 1) Synthesis L-lactide, stannous octoate were weighed into a reactor in a glove box, sealed, and taken out. An oil bath was used to heat to 135℃, and the reaction was carried out for 6h under the protection of inert gas. The polymer was collected using dichloromethane and anhydrous ethanol, and dried.

[0128] 2) Granulation Single screw granulation was used, the temperature was 190℃, and the screw speed was 36rpm.

[0129] 3) Injection Molding The granules were added to an injection molding machine, and a screw sample was obtained by injection molding, as shown inFigure 5 .

[0130] The same as example 1, except that after the synthesis and granulation, the internal fixation screw C1 is directly obtained by injection molding using an injection molding machine, without cold extrusion reinforcement. The device is subjected to a torsion test, and a peak torque of 29.49 N·mm and a peak angle of 51.40° are obtained, both of which are much smaller than the reinforced screw, as shown in Table 1. Figure 6 It is proved that the reinforcement method proposed in the application can effectively improve the torsional strength of the sample and overcome the shortcomings of high brittleness and easy breaking in torsion caused by the simple polylactic acid injection molding process.

[0131] All the documents mentioned in the present application are cited as references in the present application, as if each document is individually cited as a reference. In addition, it should be understood that various modifications or changes can be made to the present application by those skilled in the art after reading the above teaching of the present application, and these equivalent forms also fall within the scope defined by the claims attached to the present application.

Claims

1. A method of producing an internal fixation device, characterized by, The method comprises the steps of: 1) providing a first mixture comprising bioactive nanoparticles, a catalyst and a biomedical grade monomer; 2) subjecting the first mixture to a polymerization reaction to obtain a first polymer; 3) granulating the first polymer; 4) injecting the granulated product into an injection molding machine to form a first blank; 5) annealing the first blank to obtain a second blank; 6) extruding the second blank to obtain the internal fixation device; The bioactive nanoparticles are hydroxyapatite; The hydroxyapatite is modified by a silane coupling agent; The catalyst is stannous octoate; The biomedical grade monomer is selected from the group consisting of L-lactide, D-lactide, rac-lactide, glycolide, or a combination thereof; The mass content of the bioactive nanoparticles in the first mixture is 0.01-40wt%; The mass content of the catalyst in the first mixture is 0.04-0.60wt%; The mass content of the biomedical grade monomer in the first mixture is 60-99.99wt%; The bioactive nanoparticles are surface-modified, which can induce the polymerization of the biomedical grade monomer at the interface between the nanoparticles and the monomer, improve the dispersion of the nanoparticles, and retain the biological activity of the nanoparticles; The extrusion is a cold extrusion technique; The extrusion temperature is 60-200℃; The extrusion pressure is 50N-100kN; In step 6), the extrusion is repeated; The number of repetitions of the extrusion is 2-10 times; The area ratio before and after extrusion is 1-100; The bending strength of the internal fixation device is 100-300MPa; The bending modulus of the internal fixation device is 2.5-5GPa.

2. The method of claim 1, wherein, The extrusion temperature is 80-180℃.

3. The method of claim 1, wherein, The extrusion pressure is 100N-50kN.

4. The method of claim 1, wherein, The number of repetitions of the extrusion is 3-6 times.

5. The method of claim 1, wherein, The bending strength of the internal fixation device is 150-300MPa.

6. The method of claim 1, wherein, The bending strength of the internal fixation device is 250-300MPa.

7. The method of claim 1, wherein, The bending modulus of the internal fixation device is 3-4GPa.

8. The method of claim 1, wherein, The granulation has one or more characteristics selected from the group consisting of: 1) the granulation is performed using a single screw or a twin screw; 2) the granulation temperature is 40-300℃; 3) the rotation speed of the single screw or the twin screw is 20-60rpm.

9. The method of claim 1, wherein, The injection molding has one or more characteristics selected from the group consisting of: 1) the temperature of the barrel of the injection molding machine is 50-250℃; 2) the temperature of the mold is 10-150℃; 3) the injection molding time is 2-30s; 4) the injection molding pressure is 0.2-20MPa; 5) the holding pressure time is 5-100s; 6) the holding pressure is 1-20MPa.

10. The method of claim 1, wherein, The annealing has one or more characteristics selected from the group consisting of: 1) the annealing is performed together with the first blank and the mold; 2) the cooling rate of the annealing is 5-50℃ / min; 3) the cooling time of the annealing treatment is 4-15 min.

11. The method of claim 1, wherein, the cooling rate of the annealing treatment is 10-40°C / min.

12. The method of claim 1, wherein, the cooling time of the annealing treatment is 5-10 min.

13. An internal fixation device, characterized by the internal fixation device is prepared by the method of claim 1.

14. The internal fixation device of claim 13, wherein the at least one of the first and second bone anchors is a screw. the material forming the internal fixation device is selected from the group consisting of: poly-L-lactic acid, poly-DL-lactic acid, poly-L-lactide-co-glycolide.

15. The internal fixation device of claim 13, wherein the at least one screw is a bone screw. the internal fixation device is selected from the group consisting of: internal fixation compression screw, interface screw, rib rod, internal fixation plate.

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