CN111803252A - Stainless steel, preparation method thereof and drug eluting stent - Google Patents
Stainless steel, preparation method thereof and drug eluting stent Download PDFInfo
- Publication number
- CN111803252A CN111803252A CN202010877513.6A CN202010877513A CN111803252A CN 111803252 A CN111803252 A CN 111803252A CN 202010877513 A CN202010877513 A CN 202010877513A CN 111803252 A CN111803252 A CN 111803252A
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- China
- Prior art keywords
- stainless steel
- drug
- holes
- anodic oxidation
- electrolyte
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
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Images
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Landscapes
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Abstract
The invention relates to the technical field of stainless steel, in particular to stainless steel, a preparation method thereof and a drug eluting stent. The large holes and the small holes on the surface of the stainless steel provided by the invention are generated in situ and are tightly combined with the stainless steel; the big holes and the small holes on the surface of the stainless steel can be loaded with drugs, so that the purpose of double drug loading can be achieved, and the effect of slow release of the drugs can be realized. When the stainless steel provided by the invention can be applied to a drug eluting stent, the large holes can load a first drug mixed with a drug carrier, the small holes only load a second drug, the first drug in the large holes can be gradually released along with the degradation of the drug carrier, so that a slow release effect is achieved, and the second drug in the small holes can be released relatively quickly to the first drug to relieve reaction symptoms such as inflammation and the like caused by the early stage of stent implantation in vivo. The medicines in the big holes and the small holes of the stainless steel can better meet different requirements of the bracket on the medicines in the early stage and the later stage of the implantation.
Description
Technical Field
The invention relates to the technical field of stainless steel, in particular to stainless steel, a preparation method thereof and a drug eluting stent.
Background
The 316L stainless steel has good biocompatibility, mechanical property and corrosion resistance, so that the 316L stainless steel is widely applied to the medical fields of orthopedic implants, dental implants, coronary artery stents and the like. The nano overlapped hole structure is prepared on the surface of 316L stainless steel, which is beneficial to the loading of the drug and the effect of drug slow release.
Drug eluting stents can significantly reduce the rate of restenosis in blood vessels. Functional drugs such as Rapamycin (RAPA), Paclitaxel (PTX), Dexamethasone (DXM), and Hirudin (Hirudin), which are immunosuppressive drugs, are usually adopted, and the drugs are loaded into a stent metal matrix, so that after the stent is implanted into a lesion site in a body, precise release of the drugs at the local lesion site is achieved, and the purposes of inhibiting smooth muscle cell proliferation, inflammation, thrombosis and the like are achieved.
In the prior art, the controlled release of drugs on stents with nanoporous anodic alumina (Kang, HJ, Kim, DJ, Park, SJ, Yoo, JB, Ryu, ys. controlled drug release using nanoporous anodic oxide on stent [ C]Thin Solid Films 515(2007) 5184-5187) the surface of 316L stainless steel is coated with a nano-pore alumina layer so as to achieve the drug loading purpose, but the drug cannot achieve the slow release effect, and the bonding force between the alumina nano-pore layer and the matrix stainless steel is insufficient, so that the coating is easy to fall off. Titanium dioxide nanotubes on the surface of a sustained-release ibuprofen/titanium implant using composite polylactic acid (lactic acid-co-glycolic acid) ((Jia,HY，Kerr.LLSustained Ibuprofen Release Using Composite Poly(Lactic-co-GlycolicAcid)/Titanium Dioxide Nanotubes from Ti Implant Surface[J]Journal of pharmaceutical Sciences, vol.102, 2341-2348 (2013)), which uses polymer loaded drug, the slow release effect is good, but there is a problem of late thrombosis, and the polymer drug coating is easy to peel off during the operation.
Disclosure of Invention
The invention provides stainless steel, a preparation method thereof and a drug eluting stent, and solves the problems of insufficient binding force and easy falling of a drug coating and a matrix.
The specific technical scheme is as follows:
the invention provides stainless steel, wherein small holes and large holes are generated in situ on the surface of the stainless steel, and the large holes and the small holes are in a hole-overlapping structure of large holes and small holes.
In the invention, the big holes and the small holes on the surface of the stainless steel are generated in situ, so that the problem of insufficient binding force between the coating and the substrate does not exist; the big holes and the small holes on the surface of the stainless steel can be loaded with drugs, so that the effect of double drug loading is realized, and the effect of prolonging the release time of the drugs can be achieved.
In the present invention, the ratio of the pore diameters of the macropores to the pore diameters of the micropores is (18:5) - (15:1), preferably (12: 1), wherein the pore diameters of the micropores are 20nm-50nm and are suitable for loading small molecule drugs, and the pore diameters of the macropores are 180 nm-300 nm, preferably 180 nm-260 nm.
The depth of the small holes is about 4-5 μm, and the depth of the large holes is about 20-45 nm. The diameter of the big hole is big and has a certain hole depth, which can improve the binding force between the degradable polymer drug carrier and the stainless steel.
In the invention, the number of the small holes is large and the aperture is proper, so that the loading capacity of the clinically required medicine can be met.
In the present invention, the stainless steel is preferably 316L stainless steel.
The invention also provides a preparation method of the stainless steel, which comprises the following steps:
step 1: carrying out first anodic oxidation in a first electrolyte by taking stainless steel as an anode and graphite as a cathode to obtain stainless steel with a surface containing a macroporous structure;
step 2: taking the stainless steel with the surface containing the macroporous structure as an anode and graphite as a cathode, carrying out secondary anodic oxidation in a second electrolyte, and annealing to obtain the stainless steel with the macropore and the small pore and the overlapped pore structure;
the first electrolyte is sodium dihydrogen phosphate aqueous solution, potassium dihydrogen phosphate aqueous solution electrolyte or phosphoric acid aqueous solution, preferably sodium dihydrogen phosphate aqueous solution;
the second electrolyte is an alcoholic solution of ammonium fluoride.
The purpose of the first anodization of the invention is to obtain big holes on the surface of the stainless steel, and the purpose of the second anodization is to obtain small holes on the surface of the stainless steel, thereby obtaining a hole-stacked structure film with big holes sleeved with small holes.
In step 1 of the present invention, it is preferable that the stainless steel sheet be used as an anode and the graphite sheet be used as a cathode.
The stainless steel sheet is subjected to pretreatment before being subjected to the first anodic oxidation;
the pretreatment specifically comprises: and sequentially carrying out sand paper grinding, cleaning and electrochemical polishing on the stainless steel, and packaging the back of the reaction surface by using the transparent adhesive.
The grinding is step-by-step grinding by 500# -1500# abrasive paper; the cleaning is carried out for 10min under the ultrasonic condition in acetone, ethanol and deionized water respectively; in the electrochemical polishing, the polishing solution is a mixed solution of phosphoric acid and sulfuric acid, and the volume ratio is 3: 2; the polishing step comprises using stainless steel as anode and graphite as cathode, reacting for 4-6 min at a stirrer rotation speed of 760r/min and 85 deg.C with a reaction current density of 30A/dm2-50A/dm2。
In step 1 of the invention, the concentration of the first electrolyte is 0.05mol/L-0.4mol/L, preferably 0.3 mol/L;
the voltage of the first anodic oxidation is 20V-60V, preferably 30V, the time is 5min-40min, preferably 20min, the reaction temperature is 0-20 ℃, preferably 0 ℃, and the stirring speed is 350 r/min.
The first anodization of the invention can generate a macroporous structure on the surface of the stainless steel in situ under specific technological parameters.
In step 2 of the invention, the solvent in the alcoholic solution of ammonium fluoride in the second electrolyte is preferably ethylene glycol, and the concentration of the alcoholic solution of ammonium fluoride is 0.05-0.15mol/L, preferably 0.15 mol/L;
the voltage of the second anodic oxidation is 40-60V, preferably 60V, the time is 10min-60min, preferably 10min, the reaction temperature is 0-35 ℃, preferably 20 ℃, and the stirring speed is 600 r/min;
the annealing treatment is preferably carried out in the atmosphere of nitrogen or inert gas, the inert gas is preferably argon, the annealing temperature is 350-400 ℃, the heat preservation time is 40-60 min, and the temperature rise time and the temperature reduction time are 5-6 ℃/min.
According to the invention, the small hole structure can be generated on the surface of the stainless steel in situ by the second anodic oxidation under specific process parameters, and then the small hole structure and the large hole form a hole-overlapping structure.
The invention also provides application of the stainless steel or the stainless steel prepared by the preparation method in preparation of a drug eluting stent.
The present invention also provides a drug eluting stent comprising: the drug carrier and the first drug loaded in the large pores on the surface of the stainless steel, and the second drug loaded in the small pores on the surface of the stainless steel.
The drug eluting stent provided by the invention takes stainless steel as a matrix, and is low in price. The stainless steel macroporous drug carrier can make the first drug achieve the slow release effect, thereby achieving the best treatment effect. When the stent is implanted into a body, the body can generate reactions such as inflammation, and the like, and the second medicament can be quickly released to relieve inflammation because the second medicament in the small holes is not mixed with a medicament carrier. The two medicines in the medicine eluting stent better meet different requirements of the stent on the medicines in the early stage and the later stage of the stent implantation.
In the present invention, the degradable polymer is preferably chitosan or poly (lactic-co-glycolic acid) (PLGA), more preferably PLGA 75/25;
the first drug is a drug for preventing vascular restenosis, and is preferably rapamycin and/or paclitaxel;
the second drug is an anti-inflammatory drug, preferably dexamethasone.
In the invention, the macroporous structure can improve the binding force between the polymer and the stent and simultaneously reduce the burst release of the two drugs, and the first drug can be released along with the degradation of the degradable polymer. The polymer is contained in only the macropores in the stainless steel laminated pore structure, so that the using amount of the polymer is less, and the occurrence probability of late thrombus can be reduced.
In the present invention, the mass ratio of the first drug to the drug carrier is (2:8) to (4:6), preferably 3: 7.
the preparation method of the drug eluting stent comprises the following steps:
1) preparing a first drug solution: mixing a first drug with a drug carrier, and dissolving the mixture in a solvent to obtain a first drug solution;
2) preparing a second drug solution: dissolving a second drug in a solvent to obtain a second drug solution;
3) and loading the second medicine solution into the small holes of the stacked hole structure by adopting a dip coating method, drying, then continuously loading the first medicine solution into the large holes of the stacked hole structure by adopting the dip coating method, and drying to obtain the medicine eluting stent.
The silicone rubber in step 1) of the present invention is preferably 706 silicone rubber.
In step 1) of the present invention, the solvent is preferably 1, 4-dioxane; in the first drug solution, the mass concentration of the drug carrier is 1% to 2%, preferably 1%.
In step 2) of the present invention, the solvent is preferably ethanol, and the concentration of the second drug solution is 1mg/mL-2mg/mL, preferably 1 mg/mL.
In the step 3), a dip coating method is adopted to load the second medicine solution into the small holes, then the drying and the repeated operation are carried out, after the second medicine loading amount reaches a preset target value, the dip coating of the first medicine solution is carried out, and the first medicine solution is dip-coated into the large holes according to a preset value and then the drying is carried out; the second drug solution is preferably dried under vacuum in a vacuum oven at 37 ℃ for 1 hour, the first drug solution is preferably dried at ambient temperature for 24 hours, and then dried in an oven at 37 ℃ for 2 hours.
According to the technical scheme, the invention has the following advantages:
the invention provides stainless steel, wherein small holes and large holes are generated in situ on the surface of the stainless steel, and the large holes and the small holes are in a hole-overlapping structure of large holes and small holes.
The large holes and the small holes on the surface of the stainless steel provided by the invention are generated in situ and are tightly combined with the stainless steel; the big holes and the small holes on the surface of the stainless steel can be loaded with drugs, so that the effect of double drug loading is realized, and the purpose of prolonging the release time of the drugs can be achieved. When the stainless steel provided by the invention can be applied to a drug eluting stent, the large holes can load a first drug mixed with a drug carrier, the small holes only load a second drug, the first drug in the large holes can be gradually released along with the degradation of the drug carrier, so that a slow release effect is achieved, and the second drug in the small holes can be released relatively quickly to the first drug to relieve reaction symptoms such as inflammation and the like caused by the early stage of stent implantation in vivo. The medicines in the big holes and the small holes of the stainless steel can better meet different requirements of the bracket on the medicines in the early stage and the later stage of the implantation.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without inventive exercise.
FIG. 1 is a high power scanning electron microscope image of a stainless steel surface with a stacked pore structure provided in example 3 of the present invention;
FIG. 2 is a scanning electron microscope image of a stainless steel surface with a stacked pore structure provided in example 3 of the present invention;
FIG. 3 is a schematic view of two drug elution release profiles of a drug eluting stent provided in example 3 of the present invention;
FIG. 4 is a high power scanning electron micrograph of an anodized surface of stainless steel according to comparative example 1 of the present invention;
FIG. 5 is a scanning electron micrograph of a stainless steel anodized surface provided by comparative example 2 of the present invention taken at a lower magnification.
Detailed Description
In order to make the objects, features and advantages of the present invention more obvious and understandable, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it should be apparent that the embodiments described below are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In the embodiment of the invention, the water is deionized water.
Example 1
Preparation of stainless Steel of the present example in a Stack-hole Structure
An anodic oxidation process: and (3) taking the packaged stainless steel sheet as an anode, taking graphite as a cathode (50mm multiplied by 130mm), wherein the inter-polar distance is 35mm, the positive area of the cathode is larger than that of the anode, controlling the temperature by using a low-temperature constant-temperature reaction bath, and ensuring that the mass transfer and the diffusion of reactants are uniform during the oxidation of the anode, wherein the magnetic stirring rotating speed is 600 r/min. The anodic oxidation is carried out in two steps.
First step anodic oxidation: the electrolyte adopts a sodium dihydrogen phosphate/water system, wherein the concentration of the sodium dihydrogen phosphate is 0.3mol/L, a constant pressure method is adopted, the voltage is 30V, the constant temperature water bath temperature is 0 ℃, the magnetic stirring rotating speed is adjusted to be 350r/min, and the anodic oxidation time is 20 min;
the second step of anodic oxidation: the electrolyte adopts an ammonium fluoride/ethylene glycol organic electrolyte system, wherein the concentration of ammonium fluoride is 0.05M, a constant pressure method is adopted, the voltage is 40V, the constant temperature water bath temperature is 35 ℃, the anodic oxidation time is 10min, and the magnetic stirring rotating speed is adjusted to 600 r/min. After the two-step anodic oxidation reaction is finished, the prepared sample is placed in a small beaker filled with ethanol for storage, and ultrasonic cleaning is carried out in a cleaning pool for 10min so as to remove the electrolyte on the surface of the sample.
And (3) annealing the sample subjected to anodic oxidation in an argon atmosphere, wherein the annealing temperature is 350 ℃, the heat preservation time is 40min, and the heating time and the cooling time are 5 ℃/min, so that the stainless steel with the laminated hole structure is obtained.
And (3) observing the micro morphology: a field emission scanning electron microscope (Hitachi SU8010) is used for observing the surface appearance of a sample, the large holes on the surface of the stainless steel are irregular polygonal, the small holes in the large holes are honeycomb-like, the aperture reaches 20nm-60nm, and the whole structure is regular, neat and similar to a net structure.
Example 2
Preparation of stainless Steel of the present example in a Stack-hole Structure
An anodic oxidation process: and (3) taking the packaged stainless steel sheet as an anode, taking graphite as a cathode (50mm multiplied by 130mm), wherein the inter-polar distance is 35mm, the positive area of the cathode is larger than that of the anode, controlling the temperature by using a low-temperature constant-temperature reaction bath, and ensuring that the mass transfer and the diffusion of reactants are uniform during the oxidation of the anode, wherein the magnetic stirring rotating speed is 600 r/min. The anodic oxidation is carried out in two steps.
First step anodic oxidation: the electrolyte adopts a sodium dihydrogen phosphate/water system, wherein the concentration of the sodium dihydrogen phosphate is 0.3mol/L, a constant pressure method is adopted, the voltage is 30V, the constant temperature water bath temperature is 0 ℃, the magnetic stirring rotating speed is adjusted to be 350r/min, and the anodic oxidation time is 20 min;
the second step of anodic oxidation: the electrolyte adopts an ammonium fluoride/ethylene glycol organic electrolyte system, wherein the concentration of ammonium fluoride is 0.10M, a constant pressure method is adopted, the voltage is 40V, the constant temperature water bath temperature is 0 ℃, the anodic oxidation time is 60min, and the magnetic stirring rotating speed is adjusted to 600 r/min. After the two-step anodic oxidation reaction is finished, the prepared sample is placed in a small beaker filled with ethanol for storage, and ultrasonic cleaning is carried out in a cleaning pool for 10min so as to remove the electrolyte on the surface of the sample.
And (3) annealing the sample subjected to anodic oxidation in an argon atmosphere, wherein the annealing temperature is 350 ℃, the heat preservation time is 40min, and the heating time and the cooling time are 5 ℃/min, so that the stainless steel with the laminated hole structure is obtained.
And (3) observing the micro morphology: a field emission scanning electron microscope (Hitachi SU8010) is used for observing the surface appearance of a sample, the large holes on the surface of the stainless steel are similar elliptical, the small holes in the large holes are regular honeycombs, the aperture of the small holes is 20nm-50nm, and the whole structure is regular, neat and similar to a net structure.
Example 3
This example is the preparation of a stainless steel stacked hole structure
An anodic oxidation process: and (3) taking the packaged stainless steel sheet as an anode, taking graphite as a cathode (50mm multiplied by 130mm), wherein the inter-polar distance is 35mm, the positive area of the cathode is larger than that of the anode, controlling the temperature by using a low-temperature constant-temperature reaction bath, and ensuring that the mass transfer and the diffusion of reactants are uniform during the oxidation of the anode, wherein the magnetic stirring rotating speed is 600 r/min. The anodic oxidation is carried out in two steps.
First step anodic oxidation: the electrolyte adopts a sodium dihydrogen phosphate/water system, wherein the concentration of the sodium dihydrogen phosphate is 0.3mol/L, a constant pressure method is adopted, the voltage is 30V, the constant temperature water bath temperature is 0 ℃, the magnetic stirring rotating speed is adjusted to be 350r/min, and the anodic oxidation time is 20 min;
the second step of anodic oxidation: the electrolyte adopts an ammonium fluoride/ethylene glycol organic electrolyte system, wherein the concentration of ammonium fluoride is 0.15M, a constant pressure method is adopted, the voltage is 60V, the constant temperature water bath temperature is 20 ℃, the anodic oxidation time is 10min, and the magnetic stirring rotating speed is adjusted to 600 r/min. After the two-step anodic oxidation reaction is finished, the prepared sample is placed in a small beaker filled with ethanol for storage, and ultrasonic cleaning is carried out in a cleaning pool for 10min so as to remove the electrolyte on the surface of the sample.
And annealing the sample subjected to anodic oxidation at 350 ℃, keeping the temperature for 40min, and keeping the temperature rise and fall time at 5 ℃/min to obtain the stainless steel with the laminated hole structure.
And (3) observing the micro morphology: the surface morphology of the sample was observed using a field emission scanning electron microscope (hitachi SU 8010). As shown in figures 1 and 2, the large pores on the surface of the stainless steel are similar to elliptical, the small pores in the large pores are in a regular honeycomb shape, the pore diameter reaches 30nm-50nm, and the stainless steel is integrally regular and has a similar net structure.
Example 4
Preparation of stainless Steel of the present example in a Stack-hole Structure
An anodic oxidation process: and (3) taking the packaged stainless steel sheet as an anode, taking graphite as a cathode (50mm multiplied by 130mm), wherein the inter-polar distance is 35mm, the positive area of the cathode is larger than that of the anode, controlling the temperature by using a low-temperature constant-temperature reaction bath, and ensuring that the mass transfer and the diffusion of reactants are uniform during the oxidation of the anode, wherein the magnetic stirring rotating speed is 600 r/min. The anodic oxidation is carried out in two steps.
First step anodic oxidation: the electrolyte adopts a sodium dihydrogen phosphate/water system, wherein the concentration of the sodium dihydrogen phosphate is 0.3mol/L, a constant pressure method is adopted, the voltage is 30V, the constant temperature water bath temperature is 0 ℃, the magnetic stirring rotating speed is adjusted to be 350r/min, and the anodic oxidation time is 20 min;
the second step of anodic oxidation: the electrolyte adopts an ammonium fluoride/ethylene glycol organic electrolyte system, wherein the concentration of ammonium fluoride is 0.10M, a constant pressure method is adopted, the voltage is 40V, the constant temperature water bath temperature is 35 ℃, the anodic oxidation time is 10min, and the magnetic stirring rotating speed is adjusted to 600 r/min. After the two-step anodic oxidation reaction is finished, the prepared sample is placed in a small beaker filled with ethanol for storage, and ultrasonic cleaning is carried out in a cleaning pool for 10min so as to remove the electrolyte on the surface of the sample.
And annealing the sample subjected to anodic oxidation at 350 ℃, keeping the temperature for 40min, and keeping the temperature rise and fall time at 5 ℃/min to obtain the stainless steel with the laminated hole structure.
And (3) observing the micro morphology: a field emission scanning electron microscope (Hitachi SU8010) is used for observing the surface appearance of a sample, the large holes on the surface of the stainless steel are irregular, the small holes in the large holes are connected, the surface is neat and regular, and the stainless steel is of a similar net structure.
Example 5
Preparation of stainless Steel of the present example in a Stack-hole Structure
An anodic oxidation process: and (3) taking the packaged stainless steel sheet as an anode, taking graphite as a cathode (50mm multiplied by 130mm), wherein the inter-polar distance is 35mm, the positive area of the cathode is larger than that of the anode, controlling the temperature by using a low-temperature constant-temperature reaction bath, and ensuring that the mass transfer and the diffusion of reactants are uniform during the oxidation of the anode, wherein the magnetic stirring rotating speed is 600 r/min. The anodic oxidation is carried out in two steps.
First step anodic oxidation: the electrolyte adopts a sodium dihydrogen phosphate/water system, wherein the concentration of the sodium dihydrogen phosphate is 0.3mol/L, a constant pressure method is adopted, the voltage is 30V, the constant temperature water bath temperature is 0 ℃, the magnetic stirring rotating speed is adjusted to be 350r/min, and the anodic oxidation time is 20 min;
the second step of anodic oxidation: the electrolyte adopts an ammonium fluoride/ethylene glycol organic electrolyte system, wherein the concentration of ammonium fluoride is 0.05M, a constant pressure method is adopted, the voltage is 40V, the constant temperature water bath temperature is 35 ℃, the anodic oxidation time is 15min, and the magnetic stirring rotating speed is adjusted to 600 r/min. After the two-step anodic oxidation reaction is finished, the prepared sample is placed in a small beaker filled with ethanol for storage, and ultrasonic cleaning is carried out in a cleaning pool for 10min so as to remove the electrolyte on the surface of the sample.
And annealing the sample subjected to anodic oxidation at 350 ℃, keeping the temperature for 40min, and keeping the temperature rise and fall time at 5 ℃/min to obtain the stainless steel with the laminated hole structure.
And (3) observing the micro morphology: a field emission scanning electron microscope (Hitachi SU8010) is used for observing the surface appearance of a sample, the large holes on the surface of the stainless steel are irregular polygonal, the small holes inside the large holes are similar honeycomb-shaped, and part of the small holes are mutually connected, so that the whole structure is regular, neat and similar to a net structure.
Example 6
The preparation of the drug eluting stent specifically comprises the following steps:
1) a square 706 silicon rubber with the size of 10mm multiplied by 10mm is used for circling a square fixed area with the size of 10mm multiplied by 10mm on the surface of the stainless steel hole-overlapping structure in the embodiment 3, and the silicon rubber is dried for standby.
2) Preparation of rapamycin solution: mixing rapamycin and a degradable polymer PLGA70/25 according to a mass ratio of 3:7, dissolving the degradable polymer with a final concentration of 1 wt% in 1, 4-dioxane, and slowly stirring to obtain a rapamycin solution;
3) preparation of dexamethasone solution: dissolving dexamethasone into ethanol, and slowly stirring to obtain a dexamethasone solution with the concentration of 1 mg/mL;
4) loading a dexamethasone solution into a small hole in the area surrounded by the silicon rubber by adopting a dip-coating method, carrying out vacuum drying for 1h at 37 ℃, continuously loading a first drug solution into a large hole in the area surrounded by the silicon rubber by adopting the dip-coating method when the loading value of dexamethasone is 100 mu g, drying for 24h at normal temperature when the value of rapamycin is 150 mu g, and drying for 2h at 37 ℃ in a vacuum drying oven to obtain the drug eluting stent.
The step release process comprises the following steps: placing the sample after drug loading into a centrifuge tube filled with Phosphate Buffer Solution (PBS), then carrying out drug release research in a constant temperature incubator, wherein the culture temperature is 37 ℃, the step release time interval is 1h, 2h, 3h, 12h, 24h, 77h, 97h, 168h and 168h, when the same amount of new PBS solution is replaced every time, the PBS solution in the original centrifuge tube needs to be reserved for detection, and the detection is completed by an ultraviolet spectrophotometer (UV). As shown in figure 3, the respective slow release effects of dexamethasone and rapamycin are good, and the drug can be released continuously for more than three weeks.
Comparative example 1
Comparative example 1 preparation of stainless Steel
An anodic oxidation process: and (3) taking the packaged stainless steel sheet as an anode, taking graphite as a cathode (50mm multiplied by 130mm), wherein the inter-polar distance is 35mm, the positive area of the cathode is larger than that of the anode, controlling the temperature by using a low-temperature constant-temperature reaction bath, and ensuring that the mass transfer and the diffusion of reactants are uniform during the oxidation of the anode, wherein the magnetic stirring rotating speed is 600 r/min. The anodic oxidation is carried out in two steps.
First step anodic oxidation: the electrolyte adopts a sodium dihydrogen phosphate/water system, wherein the concentration of the sodium dihydrogen phosphate is 0.3mol/L, a constant pressure method is adopted, the voltage is 30V, the constant temperature water bath temperature is 0 ℃, the magnetic stirring rotating speed is adjusted to be 350r/min, and the anodic oxidation time is 20 min;
the second step of anodic oxidation: the electrolyte adopts an ammonium fluoride/ethylene glycol organic electrolyte system, wherein the concentration of ammonium fluoride is 0.15M, a constant pressure method is adopted, the voltage is 40V, the constant temperature water bath temperature is 35 ℃, the anodic oxidation time is 15min, and the magnetic stirring rotating speed is adjusted to 600 r/min. After the two-step anodic oxidation reaction is finished, the prepared sample is placed in a small beaker filled with ethanol for storage, and ultrasonic cleaning is carried out in a cleaning pool for 10min so as to remove the electrolyte on the surface of the sample.
And (3) annealing the sample subjected to anodic oxidation in an argon atmosphere, wherein the annealing temperature is 350 ℃, the heat preservation time is 40min, and the heating time and the cooling time are 5 ℃/min, so that the stainless steel is obtained.
Compared with the electrolyte concentration of the second step of anodic oxidation in the embodiment 1, the electrolyte concentration of the second step of anodic oxidation is increased, and the anodic oxidation time is prolonged, so that the surface of the stainless steel is excessively corroded, the macroporous structure is completely corroded, and the small-pore structure is not regular enough.
Comparative example 2
Comparative example 2 preparation of stainless Steel
An anodic oxidation process: and (3) taking the packaged stainless steel sheet as an anode, taking graphite as a cathode (50mm multiplied by 130mm), wherein the inter-polar distance is 35mm, the positive area of the cathode is larger than that of the anode, controlling the temperature by using a low-temperature constant-temperature reaction bath, and ensuring that the mass transfer and the diffusion of reactants are uniform during the oxidation of the anode, wherein the magnetic stirring rotating speed is 600 r/min. The anodic oxidation is carried out in two steps.
First step anodic oxidation: the electrolyte adopts a sodium dihydrogen phosphate/water (water mentioned in the text is deionized water) system, wherein the concentration of the sodium dihydrogen phosphate is 0.3mol/L, a constant pressure method is adopted, the voltage is 30V, the constant temperature water bath temperature is 0 ℃, the magnetic stirring rotating speed is adjusted to 350r/min, and the anodic oxidation time is 20 min;
the second step of anodic oxidation: the electrolyte adopts an ammonium fluoride/ethylene glycol organic electrolyte system, wherein the concentration of ammonium fluoride is 0.15M, a constant pressure method is adopted, the voltage is 40V, the constant temperature water bath temperature is 20 ℃, the anodic oxidation time is 10min, and the magnetic stirring rotating speed is adjusted to 600 r/min. After the two-step anodic oxidation reaction is finished, the prepared sample is placed in a small beaker filled with ethanol for storage, and ultrasonic cleaning is carried out in a cleaning pool for 10min so as to remove the electrolyte on the surface of the sample.
And (3) annealing the sample subjected to anodic oxidation in an argon atmosphere, wherein the annealing temperature is 350 ℃, the heat preservation time is 40min, and the heating time and the cooling time are 5 ℃/min, so that the stainless steel is obtained.
Compared with the embodiment 3, the comparative example reduces the value of reaction voltage, and causes the generated small hole structure to be irregular and the pore diameter to be different.
The above-mentioned embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the same; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. Stainless steel, characterized in that, the surface of the stainless steel generates small holes and big holes in situ, the big holes and the small holes are in a stacked hole structure of big holes and small holes;
the aperture ratio of the big holes to the small holes is (18:5) - (15: 1).
2. The stainless steel according to claim 1, wherein the depth of the small pores is 4 to 5 μm, and the depth of the large pores is 20 to 45 nm.
3. The stainless steel of claim 1, wherein the stainless steel is 316L stainless steel.
4. A method for preparing stainless steel is characterized by comprising the following steps:
step 1: carrying out first anodic oxidation in a first electrolyte by taking stainless steel as an anode and graphite as a cathode to obtain stainless steel with a surface containing a macroporous structure;
step 2: taking the stainless steel with the surface containing the macroporous structure as an anode and graphite as a cathode, carrying out secondary anodic oxidation in a second electrolyte, and annealing to obtain the stainless steel with the macropore and the small pore and the overlapped pore structure;
the first electrolyte is sodium dihydrogen phosphate aqueous solution, potassium dihydrogen phosphate aqueous solution electrolyte or phosphoric acid aqueous solution;
the second electrolyte is an alcoholic solution of ammonium fluoride.
5. The preparation method according to claim 4, wherein the voltage of the first anodic oxidation is 20V-60V, the time is 5min-40min, the reaction temperature is 0-20 ℃, and the stirring speed is 350 r/min;
the concentration of the first electrolyte is 0.05mol/L-0.4 mol/L.
6. The preparation method according to claim 4, wherein the voltage of the second anodic oxidation is 40-60V, the time is 10min-60min, the reaction temperature is 0-35 ℃, and the stirring speed is 600 r/min;
the concentration of the second electrolyte is 0.05-0.15 mol/L.
7. Use of a stainless steel according to any one of claims 1 to 3 or a stainless steel produced by the method of any one of claims 4 to 6 in the manufacture of a drug eluting stent.
8. A drug eluting stent, comprising: the stainless steel of any one of claims 1 to 3 or the stainless steel prepared by the preparation method of any one of claims 4 to 6, a drug carrier and a first drug loaded in the large pores on the surface of the stainless steel, and a second drug loaded in the small pores on the surface of the stainless steel.
9. The drug-eluting stent of claim 8, wherein the drug carrier is a degradable polymer;
the first medicament is a medicament for preventing vascular restenosis;
the second drug is an anti-inflammatory drug.
10. The drug-eluting stent of claim 8, wherein a mass ratio of the first drug to the drug carrier is (2:8) - (4: 6).
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