CN102961787B - Iron-based composite material used for full-degradation cardiovascular support and preparation method thereof - Google Patents

Abstract

The invention discloses an iron-based composite material for a fully degradable cardiovascular stent and a preparation method thereof. The iron-based composite material includes any one of Fe and W, Fe ₂ O ₃ , FeS and carbon nanotubes; by weight percentage, in the iron-based composite material, W, Fe ₂ O ₃ , FeS and carbon nanotubes The content of either in the tube is 0~10%, but not zero. The preparation method of the iron-based composite _material comprises the following steps: mixing iron powder with any one of tungsten powder, _Fe2O3 powder, FeS powder and carbon nanotube powder, and then performing discharge plasma sintering or powder metallurgy After sintering, the iron-based composite material can be obtained after cooling. The iron-based composite material for fully degradable cardiovascular stents provided by the invention avoids the problems of late thrombus and restenosis of stents that exist in traditional inert metal stents. The secondary phase harmless to the human body is selected as the reinforcing phase of the composite material, on the one hand, the corrosion rate of the iron matrix in the body fluid environment is improved, and the corrosion of the iron matrix is more uniform.

Description

A kind of fully degradable iron-based composite material for cardiovascular stent and preparation method thereof

technical field

The invention relates to an iron-based composite material for a fully degradable cardiovascular stent and a preparation method thereof.

Background technique

At present, the clinically used cardiovascular stent materials are mainly metal materials, including 316L stainless steel, Ti and Ni-Ti alloys, Co-Cr alloys, Pt-Ir alloys, and metal Ta. However, these stent materials are all biologically inert materials and are not biodegradable in vivo. After implantation, they will exist in the body as foreign bodies for a long time, and there is a risk of vascular restenosis and late thrombosis. At the same time, long-term antiplatelet therapy is required. In view of the above reasons, the development of biodegradable cardiovascular stent materials is the development trend of cardiovascular stents.

Domestic and foreign research on degradable cardiovascular stent materials focuses on magnesium alloys and pure iron. However, magnesium alloys have some disadvantages. Compared with 316L stainless steel, magnesium alloys have poor mechanical properties and may not provide enough radial support; Corrosion and fracture of the stent occurred before the molding, resulting in failure of stent implantation.

From the perspective of biocompatibility, iron is an important trace element in the human body. The iron content in the adult body is about 4-5g, of which 70% is combined with hemoglobin. Iron has important physiological functions and plays an important role in many biochemical reactions, such as oxygen sensing and transport, electron transfer, catalysis, etc. Pure iron can corrode in a body fluid environment and is expected to become a new generation of degradable cardiovascular stent materials. Early animal experiments also confirmed the good biocompatibility of pure iron and its feasibility as a cardiovascular stent material. However, pure iron still has some problems as a cardiovascular stent material. The main reason is that the mechanical properties of pure iron are slightly worse than 316L, and its mechanical properties need to be further improved ^; Pitting corrosion is prone to occur in the body fluid environment, causing the stent to lose its mechanical strength locally and rupture, resulting in implant failure. Therefore, for pure iron to be used as a cardiovascular stent material, it is necessary to accelerate its corrosion rate and at the same time make the corrosion of pure iron more uniform in the body fluid environment.

From the perspective of materials science, there are two main methods to improve the corrosion rate and corrosion mode of pure iron: one is to make the iron matrix more prone to corrosion by adding some alloying elements of non-noble metals, but studies have confirmed that this method is very effective for accelerating the corrosion of pure iron. The corrosion rate effect is not ideal; the other is to form a fine and uniformly dispersed metal interphase by adding precious metal alloying elements, which acts as an anode and iron matrix to form galvanic corrosion, which plays a role in accelerating corrosion, but using traditional casting technology, The formation and uniform distribution of metallic mesophases are difficult to control. The composite method can not only obtain a uniformly dispersed noble metal phase, accelerate the corrosion of the iron matrix, but also make the corrosion of the iron matrix more uniform from a macroscopic point of view, and further improve the mechanical properties of the iron-based material due to the strengthening effect of the secondary phase. performance.

Tungsten is the element with the highest melting point except carbon, which has a higher standard electrode potential than pure iron. Due to its better radiopacity and thrombogenicity, pure tungsten mechanically detachable microcoils are used in interventional surgery for cerebral aneurysms and other hemangiomas. The results of the study confirmed that due to the implantation of tungsten coils, although the concentration of tungsten ions in the serum of patients increased, it did not cause local or systemic toxicity. Vascular smooth muscle cells, endothelial cells and fibroblasts all showed high cell activity on the surface of pure tungsten coils, and the increase of tungsten ion concentration in the solution did not have a significant impact on cell activity. And only when the concentration of tungsten ions in the solution is higher than 50 μg/ml can it cause the toxic reaction of vascular smooth muscle cells, endothelial cells and fibroblasts. These confirmed the good biocompatibility of tungsten.

Iron oxide is a magnetic material, which has a wide range of applications in biomedical fields such as targeted delivery and cell identification. Early studies have confirmed that iron oxide has good biocompatibility. In addition, iron oxide is one of the degradation products of pure iron. Ferrous sulfide is also an iron compound and has no cytotoxicity.

Carbon nanotubes are a new type of carbon material with a special nanostructure and excellent physical and chemical properties, such as low density, high strength, good electrical conductivity and temperature conductivity, and have become a new research hotspot in the field of biomedical applications. As a reinforcement of polymer composite materials, carbon nanotubes can improve the strength of polymer materials and improve the cytocompatibility of matrix materials. Surface-modified carbon nanotubes can provide induction and support for cell growth and tissue regeneration as tissue engineering scaffolds. In addition, carbon nanotubes are also widely used in gas sensors and electrochemical analysis of biomolecules.

Contents of the invention

The purpose of the present invention is to provide a fully degradable iron-based composite material for cardiovascular stents and a preparation method thereof. The iron-based composite material has good biocompatibility and a suitable corrosion rate, and can meet the mechanical requirements of cardiovascular stent performance requirements.

A kind of fully degradable iron-based composite material for cardiovascular stent provided by the invention comprises Fe and W;

In terms of weight percentage, the content of W in the iron-based composite material is 0-10%, but not zero, and the specific composition of the iron-based composite material can be: 2%-5% by mass The composition of W and the rest of Fe may specifically be 98% Fe and 2% W, and 95% Fe and 5% W.

Another iron-based composite material for a fully degradable cardiovascular stent provided by the present invention includes Fe and Fe ₂ O ₃ ;

In terms of weight percentage, in the iron-based composite material, the content of _Fe2O3 is 0-10%, but not zero, and _the specific composition of the iron-based composite material can be: from 2% to 10% by mass Composition of 5% Fe ₂ O ₃ and the balance of Fe, specifically 98% Fe and 2% Fe ₂ O ₃ and 95% Fe and 5% Fe ₂ O ₃ .

Another iron-based composite material for a fully degradable cardiovascular stent provided by the present invention includes Fe and FeS;

In terms of weight percentage, in the iron-based composite material, the content of FeS is 0-10%, but not zero, and the specific composition of the iron-based composite material can be: 2%-5% by mass The composition of FeS and the rest of Fe can be specifically 98% Fe and 2% FeS, and 95% Fe and 5% FeS.

Another iron-based composite material for a fully degradable cardiovascular stent provided by the present invention includes Fe and carbon nanotubes;

In terms of weight percentage, in the iron-based composite material, the content of carbon nanotubes is 0-5%, but not zero, and the specific composition of the iron-based composite material can be: 0.5%-1% by mass % carbon nanotubes and the balance of Fe, specifically 99.5% Fe and 0.5% carbon nanotubes and 99% Fe and 1% carbon nanotubes.

In the above-mentioned iron-based composite material, the iron-based composite material may also include trace elements, and the trace elements are at least one of manganese, chromium, cobalt and nickel;

In the iron-based composite material, the mass percentage of the trace elements is 0-2%, but not zero;

The content of manganese, chromium, cobalt and nickel is not more than 1.5%.

In the above-mentioned iron-based composite material, the surface of the iron-based composite material is also coated with a degradable polymer drug-loaded coating;

The polymer materials in the degradable polymer drug-loaded coating are polyglycolic acid (PGA), polylactic acid (PLA), L-polylactic acid (PLLA), polycaprolactone (PCL), polycyanoacrylic acid One or more of ester (PACA), polydioxanone, polyanhydride, polyphosphazene, amino acid polymer, poly-β-hydroxybutyrate and hydroxyvalerate and their copolymers any combination of

The drug in the degradable polymer drug-loaded coating is an immunosuppressant (such as rapamycin) or an anticancer drug (such as paclitaxel);

The thickness of the degradable polymer drug-loaded coating can be 5-50 μm.

The present invention provides the preparation method of the above _- mentioned iron-based composite material, comprising the following steps: mixing iron powder with any one of tungsten powder, _Fe2O3 powder, FeS powder and carbon nanotube powder, and then sintering by discharge plasma Or powder metallurgy for sintering and cooling to obtain iron-based composite materials.

In the above preparation method, the particle size of the iron powder, tungsten powder, _Fe2O3 and FeS powder can be 100nm~ _200μm , such as 100nm~100μm, and the diameter of the carbon nanotube can be 1~100nm, such as 10 ~30nm, the length can be 1~20μm, such as 1~10μm.

In the above preparation method, the pressure of the spark plasma sintering may be 20-40 MPa, the temperature may be 750-1000° C., and the time may be 3-10 minutes, for example, sintering at 40 MPa and 950° C. for 5 minutes.

In the above preparation method, the temperature of the powder metallurgy may be 800-1400° C., and the time may be 5-10 hours.

In the above preparation method, the method further includes the step of coating the degradable polymer drug-loaded coating on the surface of the iron-based composite material;

Coating the degradable polymer drug-loaded coating by a pulling method or a uniform glue method;

The step of coating the degradable polymer drug-loaded coating by the pulling method is: first pickling the composite material, then dissolving the polymer material and drug in an organic solvent such as trichloroethane, and then The composite material is dip-coated in the polymer material and medicine, and then pulled out at a uniform speed for centrifugation to obtain a cardiovascular stent coated with a degradable polymer drug-loaded coating.

The step of coating the degradable polymer drug-loaded coating by the homogenization method is as follows: first pickling the composite material, then dissolving the polymer material and drug in an organic solvent such as trichloroethane, The above-mentioned polymer material and drug colloid are dropped on the surface of the composite material, and the colloid is spread on the composite material to form a thin layer by using a glue homogenizer at high speed, dried to remove excess solvent, and coated multiple times to achieve the best effect.

The present invention also provides the application of the above-mentioned iron-based composite material in the preparation of medical implants, and the medical implants can specifically be cardiovascular stents.

The present invention has following advantage and beneficial effect:

The iron-based composite material for fully degradable cardiovascular stents provided by the invention avoids the problems of late thrombus and restenosis of stents that exist in traditional inert metal stents. The secondary phase that is harmless to the human body is selected as the reinforcing phase of the composite material, on the one hand, the corrosion rate of the iron matrix in the body fluid environment is increased, and the corrosion of the iron matrix is more uniform; on the other hand, the addition of the secondary phase also improves The mechanical strength of iron-based composite materials can better meet the requirements of cardiovascular stents.

Description of drawings

Figure 1 shows the metallographic microstructure of iron-based composites prepared in Example 1 and Example 2, as well as cast pure iron and SPS sintered pure iron, as well as the EDS analysis of the secondary phase and matrix in the Fe-2Fe ₂ O ₃ composite.

Figure 2 shows the room temperature compression properties of iron-based composite materials and pure iron prepared in Example 1 and Example 2.

Fig. 3 is the cell survival rate of VSMC and ECV304 after cultivating 1, 2 and 4 days in the iron-based composite material prepared in embodiment 1 and embodiment 2 and casting pure iron, SPS sintered pure iron leaching solution, wherein, Fig. 3 ( a) and Figure 3(b) are the cell viability of VSMC and ECV304, respectively.

Fig. 4 shows the hemolysis rate of iron-based composite materials prepared in Example 1 and Example 2, as well as cast pure iron and SPS sintered pure iron.

Detailed ways

The experimental methods used in the following examples are conventional methods unless otherwise specified.

The materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

Embodiment 1, preparation Fe-W/Fe ₂ O ₃ /FeS composite material

Pure Fe powder (99.9wt.%, particle size 100nm~100μm), W powder (99.8%, particle size 100nm~100μm), Fe ₂ O ₃ powder (99.0%, particle size 100nm~100μm) and FeS Powder (99.0%, particle size 100nm~100μm) was used as the test raw material, which was prepared according to the secondary phase X content (mass) of 2% and 5%, respectively.

After being manually mixed in a mortar, it was mixed for 5 minutes at a speed of 2000 rpm in a mixer. Put the mixed powder in a graphite mold, and in a vacuum environment, use discharge plasma sintering technology to sinter at 950 ° C under a pressure of 40 MPa, hold for 5 minutes, and then cool to room temperature to obtain iron-based composite materials: respectively Fe-2W, Fe-5W, Fe-2Fe ₂ O ₃ , Fe-5Fe ₂ O ₃ , Fe-2FeS, and Fe-5FeS.

The metallographic microstructure of the iron-based composite material prepared in this embodiment is shown in Figure 1, wherein, _the EDS spectrum of _the secondary phase _Fe2O3 in Fe- _2Fe2O3 and the matrix Fe is also shown in Figure 1 Figure 1 (A) and Figure (B), respectively, Figure 1 also shows the metallographic microstructure of cast pure iron and SPS sintered pure iron (the sintering process conditions are the same as those in this example). It can be seen from the figure that the grain size of pure iron sintered by SPS method is significantly smaller than that of cast pure iron, and the secondary phases such as W, Fe ₂ O ₃ , FeS are evenly distributed in the iron matrix, and most of them are distributed in the grain boundary On the surface, a small part is distributed inside the grains, and the addition of the secondary phase reduces the grain size of the iron matrix to some extent.

Embodiment 2, preparation Fe-CNT composite material

Using pure Fe powder and CNT powder (diameter 10-30nm, length 1-10μm) as raw materials, according to the ratio of the added phase content of 0.5% and 1% respectively, using ethanol as a dispersant, using a stainless steel ball with a diameter of 5mm in the After ball milling and mixing for 8 hours at a rotational speed of 80 r/min, it was dried, and then sintered with the same spark plasma sintering parameters as in Example 1 to obtain a Fe-CNT composite material sample.

The metallographic microstructure of the Fe-CNT composite material prepared in this example is shown in Figure 1. It can be seen from the figure that the CNTs are uniformly distributed in the iron matrix after ball milling and sintering, and the addition of CNTs also significantly reduces the iron matrix. The grain size of the matrix.

Embodiment 3, room temperature compression performance of iron-based composite material

The composite materials prepared in Example 1 and Example 2 were prepared according to the compression test standard GB/T 7314-2005 to prepare compression samples for compression performance testing. The size of the sample was Φ2×5mm, and the compression strain rate was 2×10 ^-4 /s , since the material is a plastic material, the compressive strength is the stress value when the compressive strain is 40%.

The compressive mechanical properties of the iron-based composite materials prepared in Example 1 and Example 2 are shown in Figure 2, and the cast (As-cast) pure iron and spark plasma sintered (SPS) pure iron are used for comparison.

Embodiment 4, anti-corrosion performance of iron-based composite material

The composite material obtained in Examples 1 and 2 was wire-cut into a block sample of 10×10×2mm ³ , and polished to 2000# sandpaper. Then electrochemical tests and immersion tests were carried out in Hank's simulated body fluid at a temperature of 37°C to detect the corrosion rate of the material, and pure iron was used as a comparison.

The electrochemical parameters of the iron-based composites prepared in Example 1 and Example 2 and the corrosion rates calculated by the two detection methods are shown in Table 1. As can be seen from the data in Table 1, the electrochemical test results show that The corrosion rate of pure iron sintered by SPS is faster than that of cast pure iron. At the same time, the addition of the second phase composition significantly increases the corrosion rate of iron-based materials. The higher the content of the second phase, the faster the corrosion rate of iron-based materials. The immersion test results show that the corrosion rate of the composite material after the addition of W, Fe ₂ O ₃ , and FeS is comparable to that of pure iron, while the addition of CNT significantly improves the corrosion rate of the iron-based material.

Table 1 Electrochemical test parameters of Fe-based composites and corrosion rates calculated by electrochemical and immersion tests

V _corr : corrosion potential; I _corr : corrosion current; υ _corr : corrosion rate

Embodiment 5, the biocompatibility of iron-based composite material

Prepare the experimental sample according to the method in Example 4, compare pure iron and SPS sintered pure iron, extract the leaching solution according to the standard of ^{1.25cm2ml -1} according to the surface area/leaching solution volume ratio after being sterilized by ultraviolet radiation, Cytotoxicity experiments of vascular smooth muscle cells VSMC and endothelial cells ECV304 were performed. In addition, add the sample to 10ml of normal saline containing 0.2ml of diluted human blood (normal saline: human blood (volume) = 5:4) and soak for 1 hour to test the hemolysis rate of the material.

The results of the cell survival rate and the hemolysis rate of various composite materials relative to the negative control after culture are shown in Figure 3 and Figure 4 respectively. After 4 days, the survival rate of VSMC cells decreased with the prolongation of culture time, while ECV304 cells still maintained a high survival rate after 4 days of culture, indicating that all iron-based composite materials and pure iron have certain effects on vascular smooth muscle cells. It has no toxicity to endothelial cells and is suitable for application as a vascular stent material. It can be seen from Figure 4 that the hemolysis rate of all iron-based composite materials and pure iron materials is about 3%, which is lower than the threshold standard of 5% for blood compatibility.

Example 6, preparation of iron-based composite material loaded with PLLA degradable coating

The iron-based composite material was prepared according to Example 2, and then coated with L-polylactic acid (PLLA) and paclitaxel drug coating on its surface according to the following pulling method to prepare PLLA and paclitaxel surface-modified materials:

(1) Use concentrated nitric acid and hydrofluoric acid to prepare pickling solution, and pickle the composite material for 20 minutes.

(2) Dissolve 0.5g PLLA (molecular weight: 200kDa) and 15mg paclitaxel in 10ml trichloroethane.

(3) Put the acid-washed composite material into the colloid and soak it for 30 minutes, then pull it out at a constant speed, and dry it overnight in vacuum at room temperature. The thickness of the PLLA degradable coating obtained according to the above examples is 10-30 μm.

Claims (13)

1. an iron base composite material, is characterized in that: by weight percentage, and described iron base composite material is that the W of 2% ~ 5% and the Fe of surplus form by mass percentage;

The preparation method of described iron base composite material, comprises the steps: iron powder to mix with tungsten powder, then through discharge plasma sintering, namely obtains iron base composite material through cooling;

The pressure of described discharge plasma sintering is 20 ~ 40MPa, and temperature is 750 ~ 1000 DEG C, and the time is 3 ~ 10min.

2. an iron base composite material, is characterized in that: by weight percentage, and described iron base composite material is the Fe of 2% ~ 5% by mass percentage ₂o ₃form with the Fe of surplus;

The preparation method of described iron base composite material, comprises the steps: iron powder and Fe ₂o ₃powder mixes, and then through discharge plasma sintering, namely obtains iron base composite material through cooling;

The pressure of described discharge plasma sintering is 20 ~ 40MPa, and temperature is 750 ~ 1000 DEG C, and the time is 3 ~ 10min.

3. a full iron base composite material, is characterized in that: by weight percentage, and described iron base composite material is that the FeS of 2% ~ 5% and the Fe of surplus form by mass percentage;

The preparation method of described iron base composite material, comprises the steps: iron powder to mix with FeS powder, then through discharge plasma sintering, namely obtains iron base composite material through cooling;

The pressure of described discharge plasma sintering is 20 ~ 40MPa, and temperature is 750 ~ 1000 DEG C, and the time is 3 ~ 10min.

4. an iron base composite material, is characterized in that: by weight percentage, and described iron base composite material is that the CNT of 0.5% ~ 1% and the Fe of surplus form by mass percentage;

In described iron base composite material, the content of CNT is 0 ~ 5%, but non-vanishing, and carbon nanotube diameter is 1 ~ 100nm, and length is 1 ~ 20 μm;

The preparation method of described iron base composite material, comprises the steps: iron powder to mix with described carbon nanotube powder, then through discharge plasma sintering, namely obtains iron base composite material through cooling;

The pressure of described discharge plasma sintering is 20 ~ 40MPa, and temperature is 750 ~ 1000 DEG C, and the time is 3 ~ 10min.

5. the iron base composite material according to any one of claim 1-4, is characterized in that: described iron base composite material also comprises trace element, and described trace element is at least one in manganese, chromium, cobalt and nickel;

In described iron base composite material, the mass percentage of described trace element is 0 ~ 2%, but non-vanishing;

The content of described manganese, chromium, cobalt and nickel is all not more than 1.5%.

6. the iron base composite material according to any one of claim 1-4, is characterized in that: the surface of described iron base composite material is also coated with degradable macromolecule drug-carried coat;

Macromolecular material in described degradable macromolecule drug-carried coat is one or more the combination in any in polyglycolic acid, polylactic acid, PLLA, polycaprolactone, polybutylcyanoacrylate, poly-para-dioxane ketone, condensing model, poly phosphazene, polymer-amino-acid, poly-β-hybroxybutyric acid and hydroxyl valerate and copolymer thereof;

Medicine in described degradable macromolecule drug-carried coat is immunosuppressant or cancer therapy drug;

The thickness of described degradable macromolecule drug-carried coat is 5 ~ 50 μm.

7. the preparation method of iron base composite material described in claim 1, comprises the steps: iron powder to mix with tungsten powder, then through discharge plasma sintering, namely obtains iron base composite material through cooling.

8. the preparation method of iron base composite material described in claim 2, comprises the steps: iron powder and Fe ₂o ₃powder mixes, and then through discharge plasma sintering, namely obtains iron base composite material through cooling.

9. the preparation method of iron base composite material described in claim 3, comprises the steps: iron powder to mix with FeS powder, then through discharge plasma sintering, namely obtains iron base composite material through cooling.

10. the preparation method of iron base composite material described in claim 4, comprises the steps: iron powder to mix with described carbon nanotube powder, then through discharge plasma sintering, namely obtains iron base composite material through cooling.

The preparation method of 11. iron base composite materials according to any one of claim 7-10, it is characterized in that: described iron base composite material also comprises trace element, described trace element is at least one in manganese, chromium, cobalt and nickel;

In described iron base composite material, the mass percentage of described trace element is 0 ~ 2%, but non-vanishing;

The content of described manganese, chromium, cobalt and nickel is all not more than 1.5%.

The preparation method of 12. iron base composite materials according to any one of claim 7-10, is characterized in that: described method also comprises the step of the surface-coated degradable macromolecule drug-carried coat to described iron base composite material;

Described degradable macromolecule drug-carried coat is applied by czochralski method or even glue method;

Macromolecular material in described degradable macromolecule drug-carried coat is one or more the combination in any in polyglycolic acid, polylactic acid, PLLA, polycaprolactone, polybutylcyanoacrylate, poly-para-dioxane ketone, condensing model, poly phosphazene, polymer-amino-acid, poly-β-hybroxybutyric acid and hydroxyl valerate and copolymer thereof;

Medicine in described degradable macromolecule drug-carried coat is immunosuppressant or cancer therapy drug;

The thickness of described degradable macromolecule drug-carried coat is 5 ~ 50 μm.

Iron base composite material according to any one of 13. claim 1-6 is preparing the application in medical implant.