CN114176855B - Degradable polymer ultrathin membrane, preparation method and application thereof, and preparation method of covered vascular stent - Google Patents
Degradable polymer ultrathin membrane, preparation method and application thereof, and preparation method of covered vascular stent Download PDFInfo
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- CN114176855B CN114176855B CN202111517732.4A CN202111517732A CN114176855B CN 114176855 B CN114176855 B CN 114176855B CN 202111517732 A CN202111517732 A CN 202111517732A CN 114176855 B CN114176855 B CN 114176855B
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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Abstract
The invention provides a degradable polymer ultrathin membrane, a preparation method and application thereof, and a preparation method of a covered vascular stent. The invention adopts a specific degradable polyester and polyethylene glycol copolymer as raw materials to prepare an ultrathin film, and performs stretching orientation in the film preparation process to form an ultrathin film with an orientation groove structure on the surface, and finally winds the ultrathin film on the surface of a vascular stent. Through the mode, the film has good self-adhesion property, so that the film can be firmly adhered to the vascular stent and is not easy to fall off; the coating has good flexibility, and the coating stent can smoothly pass through a tortuous blood vessel; the good toughness of the coating can ensure that the coating does not crack after the stent is opened. In addition, the orientation structure on the surface of the tectorial membrane can promote the adhesion of endothelial cells on the stent and guide the oriented growth of the endothelial cells, the PEG component in the tectorial membrane can play a role in lubrication during the implantation of the stent, the anticoagulation performance of the stent is improved, and the formation of thrombus inside the stent is slowed down.
Description
Technical Field
The invention relates to the field of medical materials, in particular to a degradable polymer ultrathin film, a preparation method and application thereof, and a preparation method of a covered vascular stent.
Background
Coronary artery perforation refers to tearing of blood vessels in percutaneous arterial interventional procedures, which causes leakage of contrast agent or blood from the arterial tear to outside of the blood vessels, resulting in heart tamponade, coronary ventricular fistula, myocardial infarction, etc. in a short time in patients, which can often endanger the life of the patient. In addition, common vascular diseases such as aneurysms, vascular ruptures, vascular perforations, and the like, can also cause acute bleeding, leading to life hazards for the patient. Aiming at the problems, a treatment method of an intravascular interventional stent graft is often adopted clinically. The method has the advantages of small wound, less complication, high safety, less pain of patients, etc. The specific process is mainly that the covered stent in a compressed state is delivered to the position of the vascular lesion, and is released after being positioned accurately, the expanded covered stent can cover the lesion vessel, isolate the vascular lesion part and form a new blood flow channel, thereby achieving the treatment purpose.
The covered stent is one of important instruments for treating serious complications such as vascular malformed lesions, acute and chronic vascular injuries and the like. At present, a stent and a membranous-combined covered stent are mainly used for plugging a vascular lesion clinically. The membrane material is generally autologous blood vessel, animal pericardium or non-degradable polymer, and is fixed on the surface of the bracket by stitching, pressing and holding, etc. However, the above stent graft has some problems, such as: (1) Because the coating is not degradable, the coating exists as a foreign body for a long time and blocks the endothelialization process of the blood vessel, thereby causing restenosis and thrombosis in the long-term stent; (2) Because the coating is thicker, the coating stent is often poorer in flexibility, so that the stent is difficult to pass through a tortuous blood vessel or is easy to damage the blood vessel; (3) The combination of the covering film and the bracket is not firm, and the shifting, falling off or internal leakage is easy to occur; (4) the xenogeneic pericardium is at risk of disease transmission, etc.
Therefore, research and development of a stent graft with good performance has become a key technical problem to be solved in social development. Patent application CN106937895A, CN104490502A, CN101627933B, CN106667621a discloses a degradable covered stent prepared from degradable polymers such as polylactic acid, polycaprolactone, collagen, polysaccharide and the like. However, in these schemes, there are also the following problems: 1. the thickness of the coating is large, and is mostly in the order of micrometers (tens or even hundreds of micrometers), so that the coating stent is often poor in flexibility, and is difficult to pass through tortuous blood vessels or is easy to damage the blood vessels. 2. The coating film is combined with the bracket in a seam or adhesive mode; while it is technically difficult to suture small-sized stents, small-diameter vessels are precisely the most prone to sudden diseases such as coronary artery perforation. The adhesive mode is easy to cause the phenomenon that the combination of the tectorial membrane and the bracket is not firm, and the displacement, the falling-off or the internal leakage occur.
Therefore, the coated stent still has the problems of complex preparation process, poor flexibility, large outer diameter size, poor bonding firmness of the coated film (additional fixation is needed), high requirements on the tear resistance of the coated film and the like.
Disclosure of Invention
In view of the above, the present invention aims to provide a degradable polymer ultrathin membrane, a preparation method and an application thereof, and a preparation method of a covered stent. The degradable polymer ultrathin film provided by the invention can effectively improve the flexibility, the bonding fastness and the use effect of the tectorial membrane bracket.
The invention provides a preparation method of a degradable polymer ultrathin film, which comprises the following steps:
a) Dissolving a degradable high polymer material in a solvent to obtain a precursor solution;
b) Preparing a film from the precursor solution to obtain a base film;
c) And stretching and orienting the base film to obtain the degradable coating film.
Preferably, the conditions of the stretch orientation are: stretching orientation is carried out at a stretching speed of 1-100 cm/s, and the ambient temperature is 10-75 ℃.
Preferably, the degradable polymer is a copolymer of degradable polyester and polyethylene glycol.
Preferably, in the copolymer of the degradable polyester and the polyethylene glycol, the polyester is selected from one or more of polylactic acid, polyglycolide, polycaprolactone and polydioxanone, or is selected from the copolymer of at least two of polylactic acid, polyglycolide, polycaprolactone and polydioxanone.
Preferably, in the step b), the film forming mode is spin coating, doctor blading or casting;
the spin coating operation is as follows: the precursor solution is dripped on a plane substrate, and the precursor solution is rotated for 5 to 2000s at 100 to 15000rpm and removed from the solvent at 5 to 100 ℃ to obtain a base film;
in the step a):
the solvent is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, acetone, ethyl acetate, 1, 4-dioxane, benzene, toluene, N-dimethylformamide and N-methylpyrrolidone;
the concentration of the degradable high polymer material in the solvent is 1-1500 mg/mL.
Preferably, in the step a), a medicine or an active factor for anticoagulation/regulation of vascular endothelial growth is added during the feeding;
the anticoagulant/vascular endothelial growth regulating medicine or active factor is one or more selected from heparin, hirudin, taxol, rapamycin, sirolimus and derivatives thereof, polypeptide and glycogen synthase kinase 3 beta inhibitor.
The invention also provides the degradable polymer ultrathin film prepared by the preparation method in the technical scheme.
The invention also provides an application of the degradable polymer ultrathin film as a tectorial membrane in a tectorial membrane vascular stent, wherein the degradable polymer ultrathin film is the degradable polymer ultrathin film in the technical scheme.
The invention also provides a preparation method of the covered vascular stent, which comprises the following steps:
winding the degradable polymer ultrathin film on a vascular stent to obtain a covered vascular stent;
the degradable polymer ultrathin film is the degradable polymer ultrathin film in the technical scheme.
Preferably, in the covered stent, the number of winding layers of the degradable polymer ultrathin film on the stent is 1-1000, and the total thickness is 0.01-100 μm.
The invention adopts the copolymer of degradable polyester and polyethylene glycol as raw materials to prepare the ultrathin film, and performs stretching orientation in the film preparation process to form the ultrathin film with an orientation groove structure on the surface, and the ultrathin film is compounded on the surface of the vascular stent in a simple winding mode. Through the mode, the film has good self-adhesion property, so that the film can be firmly adhered to the vascular stent and is not easy to fall off; the coating has good flexibility, and the coating stent can smoothly pass through a tortuous blood vessel; the good toughness of the coating can ensure that the coating does not crack after the stent is opened. In addition, the orientation structure on the surface of the tectorial membrane can promote the adhesion of endothelial cells on the stent and guide the oriented growth of the endothelial cells, and the hydrophilic PEG component in the tectorial membrane can play a role in lubrication during the implantation of the stent, improve the anticoagulation performance of the stent and slow down the formation of thrombus inside the stent.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and that other drawings can be obtained according to the provided drawings without inventive effort for a person skilled in the art.
FIG. 1 is an optical microscope view of a PLA-PEG based ultrathin film sample;
FIG. 2 is an optical microscope view of a stretched PLA-PEG based ultrathin film sample;
FIG. 3 is a fluorescence microscopy image of a PLA-PEG based ultrathin film sample;
FIG. 4 is a fluorescence microscopy image of a stretched PLA-PEG based ultrathin film sample;
FIG. 5 is a graph showing the effect of APTT test in example 1;
FIG. 6 is a graph showing the effect of APTT test in example 6.
Detailed Description
The invention provides a preparation method of a degradable polymer ultrathin film, which comprises the following steps:
a) Dissolving a degradable high polymer material in a solvent to obtain a precursor solution;
b) Preparing a film from the precursor solution to obtain a base film;
c) And stretching and orienting the base film to obtain the degradable coating film.
Regarding step a):
In the invention, the degradable polymer is a copolymer of degradable polyester and polyethylene glycol. Wherein the polyester segment is selected from one or more of polylactic acid, polyglycolide, polycaprolactone and polydioxanone, or a copolymer of at least two substances selected from polylactic acid, polyglycolide, polycaprolactone and polydioxanone. In some embodiments of the invention, the copolymer of the degradable polyester and polyethylene glycol is a PLA-PEG copolymer, a caprolactone lactide and PEG copolymer (PCLA-PEG), a polydioxanone and polyethylene glycol copolymer (PPDO-PEG). The invention prepares the ultrathin film by taking the degradable polyester and polyethylene glycol copolymer as raw materials for covering the vascular stent, and the covering film prepared by the material can slow down the formation of thrombus inside the stent. In the present invention, the source of the copolymer of the degradable polyester and polyethylene glycol is not particularly limited, and is generally commercially available or may be prepared according to a conventional preparation method well known to those skilled in the art. In the present invention, the number average molecular weight of the copolymer of the degradable polyester and the polyethylene glycol is preferably 500 to 1000000; in the copolymer of the degradable polyester and the polyethylene glycol, the ratio of the number average molecular weight of the degradable polyester segment to the number average molecular weight of the polyethylene glycol segment is 1:0.00001-1.
In the invention, the solvent is a good solvent of a degradable polymer material, preferably one or more of dichloromethane, chloroform, tetrahydrofuran, acetone, ethyl acetate, 1, 4-dioxane, benzene, toluene, N-dimethylformamide and N-methylpyrrolidone. The concentration of the degradable high polymer material in the solvent is 1-1500 mg/mL.
The invention has no special limitation on the mixing mode of dissolving the degradable polymer material in the solvent, and the degradable polymer material is uniformly mixed and dissolved according to the conventional mixing means in the field.
In the invention, drugs or active factors for anticoagulation/regulation of vascular endothelial growth can also be added in the mixing process. In the invention, the anticoagulant/vascular endothelial growth regulating drug or active factor is one or more selected from heparin, hirudin, paclitaxel, rapamycin, sirolimus and derivatives thereof, polypeptide and glycogen synthase kinase 3 beta inhibitor. In the present invention, the concentration of the anticoagulant/vascular endothelial growth-regulating drug or active factor in the precursor solution is preferably 0.001-1000 mg/mL, and in some embodiments 0.1mg/mL.
And (3) after the materials are mixed, obtaining a precursor solution.
Regarding step b):
The film forming method is preferably spin coating, doctor blading or casting. Wherein, the spin coating operation is: and (3) dropwise adding the precursor solution on a planar substrate, and removing the solvent at the temperature of 5-100 ℃ by rotating at 100-15000 rpm for 5-2000 s to obtain the base film. The operation of the doctor blade method and the casting method is not particularly limited, and may be performed in a conventional manner in the art.
Regarding step c):
The conditions of the stretch orientation are preferably: stretching orientation is carried out at a stretching speed of 1-100 cm/s, and the ambient temperature is 10-75 ℃. Under the stretching orientation condition, the surface of the obtained ultrathin film can form a specific oriented groove structure, which is beneficial to adhesion of endothelial cells and guiding the oriented growth of the endothelial cells. In some embodiments of the invention, the stretching speed is 5cm/s, 20cm/s, 50cm/s or 100cm/s. In some embodiments of the invention, the ambient temperature is room temperature (25 ℃) or 50 ℃.
In the present invention, after the above stretching treatment, the obtained degradable polymer ultrathin film has an oriented structure, specifically an oriented groove structure, see fig. 2.
The invention also provides the degradable polymer ultrathin film prepared by the preparation method in the technical scheme.
The invention provides an application of a degradable polymer ultrathin film as a tectorial membrane in a tectorial membrane vascular stent, wherein the degradable polymer ultrathin film is the degradable polymer ultrathin film in the technical scheme.
In the present invention, the thickness of the degradable polymer ultrathin film is 0.001-10 μm, preferably 0.01-1 μm. In the prior art, the thickness of a single-layer film in the tectorial membrane is tens micrometers or even hundreds micrometers, and the thickness is thicker, so that the tectorial membrane bracket is often poorer in flexibility, and is difficult to pass through tortuous blood vessels or is easy to damage the blood vessels. The ultrathin film of the invention has the thickness of less than 10 mu m, can effectively overcome the problems, has good flexibility and toughness, and can prevent the tectorial membrane from cracking after the stent is opened.
The invention also provides a preparation method of the covered vascular stent, which comprises the following steps: winding the degradable polymer ultrathin film on a vascular stent to obtain a covered vascular stent;
the degradable high polymer ultrathin film is the degradable high polymer ultrathin film in the technical scheme.
In the invention, in the covered stent, the degradable polymer ultrathin film is covered on the surface of the stent by a simple winding mode. In the prior art, the coating is combined with the stent in a seam or gluing mode, so that the problems of difficult suturing of the small-size stent and infirm combination exist, but the invention combines in a simple winding mode, and the coating can be firmly covered on the vascular stent by utilizing the good self-adhesion of the ultrathin film, so that the operation is easy, and the stent is not easy to deform. The winding operation is specifically as follows: contacting the vascular stent with the film, and then covering the surface of the stent with the film while rotating; the number of winding layers of the film is controlled according to actual needs.
In the present invention, the number of winding layers of the degradable polymer ultrathin film on the vascular stent is 1 to 1000, and the total thickness is 0.01 to 100 μm, more preferably 10 μm or less. The degradable polymer ultrathin film adopted by the invention is wound into the thickness by the layer number, and still can show good flexibility and bonding firmness.
The invention also provides a covered stent prepared by the preparation method in the technical scheme.
Compared with the prior art, the invention adopts the copolymer of the degradable polyester and the polyethylene glycol as the raw material to prepare the ultrathin film, and the ultrathin film is stretched and oriented in the film preparation process to form the ultrathin film with the oriented groove structure on the surface, and the ultrathin film is compounded on the surface of the vascular stent in a simple winding mode. Through the mode, the formation of thrombus inside the stent can be slowed down, endothelial cells can be adhered to and oriented to grow, the coating can be firmly adhered to the vascular stent and is not easy to fall off, the coating has good flexibility, and the coating can not be broken after the stent is expanded through the tortuous blood vessel. The hydrophilic PEG component in the coating can play a role in lubrication during stent implantation and improve the anticoagulation performance of the stent.
For a further understanding of the present invention, preferred embodiments of the invention are described below in conjunction with the examples, but it should be understood that these descriptions are merely intended to illustrate further features and advantages of the invention, and are not limiting of the claims of the invention. In the examples below, the room temperature is 25 ℃.
Example 1
1. Sample preparation
S1, dissolving PLA-PEG copolymer in dichloromethane to form a precursor solution with the concentration of 50 mg/mL.
S2, 200 mu L of precursor solution is dripped on a clean silicon wafer, and the silicon wafer is rotated for 30S at 2000rpm and then dried at room temperature to obtain a PLA-PEG ultrathin film (the thickness is 0.85 mu m).
And S3, stretching and orienting the PLA-PEG ultrathin film, wherein the condition is that the stretching and orienting are carried out at room temperature at a stretching speed of 20cm/S, and a degradable coating film (the thickness is 0.78 mu m) is obtained.
S4, winding the obtained degradable coating on a vascular stent, wherein the number of winding layers is 10, and the total thickness is about 7.8 mu m. Obtaining the covered stent.
2. Sample characterization and testing
(1) Mechanical property test
The mechanical properties of the non-stretched ultrathin film (referred to as PLA-PEG ultrathin film) obtained in the step S2, the stretched ultrathin film (referred to as stretched PLA-PEG ultrathin film) obtained in the step S3, and the solution-cast PLA-PEG film were tested, respectively, and the results are shown in Table 1.
TABLE 1 mechanical Properties of ultra-thin films
Thickness (μm) | Tensile Strength (MPa) | Elongation at break (%) | |
PLA-PEG ultrathin film | 0.85 | 73.0±1.7 | 156.7±9 |
Stretched PLA-PEG ultrathin film | 0.78 | 91.6±4.8 | 214.2±22 |
Solution casting PLA-PEG film | 55.47 | 41.5±3.5 | 86±1.5 |
Note that: in Table 1, "PLA-PEG ultrathin film" means an unstretched ultrathin film obtained in step S2 of example 1; the term "stretched PLA-PEG ultrathin film" refers to the ultrathin film obtained in the step S3 in the example 1 after the stretching treatment; "solution cast PLA-PEG film" refers to a film made by film formation by a solution casting process.
Table 1 the tensile properties of the films test results show that: compared with the PLA-PEG film cast by solution, the PLA-PEG ultrathin film has higher tensile strength and elongation at break, and the tensile strength and elongation at break of the ultrathin film after stretching orientation are further improved. The above results demonstrate that a film prepared with an ultrathin film of stretched PLA-PEG will have better strength and toughness and will not be easily broken.
(2) Adhesion test
PLA-PEG ultrathin film, stretched PLA-PEG ultrathin film and solution casting PLA-PEG film were respectively attached on 316L stainless steel sheet, and the adhesion of the polymer film to the stainless steel substrate was examined by a cross-cut method (GB/T9286-1998, cross-cut test of paint film of color paint and varnish), and the experimental results are shown in Table 2.
Table 2 adhesion test results
As can be seen from the test results in Table 2, the adhesion force of the PLA-PEG and the stretched PLA-PEG ultrathin film is obviously higher than that of the solution casting PLA-PEG film, which proves that the PLA-PEG ultrathin film has better flexibility and adhesion, and the combination of the film prepared by the ultrathin film and the metal bracket is firmer.
(3) Observation by optical microscope
In a 24-well plate, coronary endothelial cells were seeded onto the surface of the film sample at a seeding density of 1.5X10 4 cell/well and static culture in a constant temperature incubator (5% CO 2 37 ℃ for 24 hours.
The above-described test was performed using a PLA-PEG ultrathin film and a stretched PLA-PEG ultrathin film as film samples, respectively, and the results were shown in fig. 1 and 2 (the scale in the figures is 100 μm in fig. 1-2), respectively, fig. 1 is an optical microscope view of a PLA-PEG ultrathin film-based sample, and fig. 2 is an optical microscope view of a stretched PLA-PEG ultrathin film-based sample. It can be seen that the ultra-thin film can form an oriented groove structure after being stretched and oriented; the number of endothelial cells that adhere and grow on the stretched PLA-PEG ultrathin film is greater than that of the PLA-PEG ultrathin film, which indicates that the coating film prepared by stretching the ultrathin film is more beneficial to the adhesion and growth of endothelial cells on the stent.
(4) Fluorescent microscope observation
In a 24-well plate, coronary endothelial cells were seeded onto the surface of the film sample at a seeding density of 1.5X10 4 cell/well and static culture in a constant temperature incubator (5% CO 2 37 ℃ for 48 hours. Cells were stained with FDA and incubated for 2 min in the dark and then visualized by fluorescence microscopy.
The above-described test was performed using a PLA-PEG ultrathin film and a stretched PLA-PEG ultrathin film as film samples, respectively, and the results were shown in fig. 3 and fig. 4 (in fig. 3-4, the scale is 50 μm), respectively, fig. 3 is a fluorescence microscopy image based on the PLA-PEG ultrathin film sample, and fig. 4 is a fluorescence microscopy image based on the stretched PLA-PEG ultrathin film sample. It can be seen that the number of adherent growth of endothelial cells on the stretched PLA-PEG ultrathin film is significantly greater and that the cells have a tendency to orient along the groove structure of the film surface, indicating that a coating prepared with the stretched ultrathin film would be expected to guide the oriented growth of endothelial cells on the stent.
(5) Partial prothrombin time (Activated Partial Thromboplastin Time, APTT)
The APTT test is a simple, reliable method of detecting the endogenous coagulation system. The collected blood and sodium citrate anticoagulant were mixed in a volume ratio of 9:1 and evaluated within 12 hours. Platelet poor plasma was obtained by centrifugation of whole blood at 3000 rpm for 15 minutes. Samples were placed in 24-well plates, 500 μl of platelet poor plasma was added to each well and incubated at 37 ℃ for 30 minutes, and the incubated platelet poor plasma was then detected by an automatic coagulometer.
The above tests were performed using 316L stainless steel, PLA ultrathin film, PLA-PEG ultrathin film as samples, respectively, and the results of the APTT test are shown in fig. 5, and fig. 5 is an effect graph of the APTT test in example 1 (P < 0.05). Compared with 316L stainless steel, the APTT result of the PLA ultrathin film is not obviously changed, and the APTT result of the PLA-PEG ultrathin film is obviously prolonged, which indicates that the PEG component in the ultrathin film can obviously prolong the coagulation time of the material, so that the material has good anticoagulation performance, and therefore, the coating film prepared by the PLA-PEG ultrathin film is expected to slow down the formation of thrombus in a stent.
Example 2
1. Sample preparation
S1, dissolving PLA-PEG copolymer in acetone to form a precursor solution with the concentration of 500mg/mL.
S2, 100 mu L of precursor solution is dripped on a clean silicon wafer, and the silicon wafer is rotated for 30S at 2000rpm and then dried at room temperature to obtain a PLA-PEG ultrathin film (the thickness is 1.74 mu m).
And S3, stretching and orienting the PLA-PEG ultrathin film, wherein the condition is that the stretching and orienting are carried out at room temperature at a stretching speed of 5cm/S, and a degradable coating film (the thickness is 1.58 mu m) is obtained.
S4, winding the obtained degradable coating on a vascular stent, wherein the number of winding layers is 2, and the total thickness is about 3.16 mu m. Obtaining the covered stent.
Example 3
1. Sample preparation
S1, dissolving PLA-PEG copolymer in N-methyl pyrrolidone to form a precursor solution with the concentration of 10 mg/mL.
S2, 200 mu L of precursor solution is dripped on a clean silicon wafer, and the silicon wafer is rotated for 30S at 15000rpm and then dried at room temperature to obtain a PLA-PEG ultrathin film (the thickness is 0.41 mu m).
And S3, stretching and orienting the PLA-PEG ultrathin film under the condition that the stretching and orienting are carried out at the stretching speed of 50cm/S at the temperature of 50 ℃ to obtain the degradable coating film (the thickness is 0.33 mu m).
S4, winding the obtained degradable coating on a vascular stent, wherein the number of winding layers is 100, and the total thickness is about 33 mu m. Obtaining the covered stent.
Example 4
1. Sample preparation
S1, dissolving a copolymer of caprolactone lactide and PEG (PCLA-PEG) in toluene to form a precursor solution with the concentration of 1000 mg/mL.
S2, 100 mu L of precursor solution is dripped on a clean silicon wafer, and the silicon wafer is rotated for 30S at 10000rpm and then dried at room temperature, so as to obtain the PCLA-PEG ultrathin film (the thickness is 0.08 mu m).
S3, stretching and orienting the PCLA-PEG ultrathin film under the condition that the stretching and orienting are carried out at room temperature at a stretching speed of 5cm/S, so as to obtain the degradable coating film (the thickness is 0.05 mu m).
S4, winding the obtained degradable coating on a vascular stent, wherein the number of winding layers is 5, and the total thickness is about 0.25 mu m. Obtaining the covered stent.
Example 5
1. Sample preparation
S1, dissolving a copolymer of p-polydioxanone and polyethylene glycol (PPDO-PEG) in N, N-dimethylformamide to form a precursor solution with the concentration of 1500mg/mL.
S2, 200 mu L of precursor solution is dripped on a clean silicon wafer, and the silicon wafer is rotated for 30S at 10000rpm and then dried at room temperature to obtain a PPDOPEG ultrathin film (thickness is 1.85 mu m).
S3, stretching and orienting the PPDO-PEG ultrathin film under the condition that the stretching and orienting are carried out at the room temperature at the stretching speed of 100cm/S, so as to obtain the degradable coating film (the thickness is 1.60 mu m).
S4, winding the obtained degradable coating on a vascular stent, wherein the number of winding layers is 5, and the total thickness is about 8.0 mu m. Obtaining the covered stent.
Example 6: performance testing
(1) Mechanical property test
The mechanical properties of the ultra-thin films obtained after stretching in examples 2 to 5 were tested, and the results are shown in Table 3.
TABLE 3 mechanical Properties of stretched ultra-thin films
As can be seen from the test results in Table 3, the stretched ultrathin film prepared by the invention has excellent strength and toughness, and is not easy to break.
(2) Adhesion test
The ultra-thin films obtained after stretching in examples 2 to 5 were tested according to the test method of example 1, and the results are shown in table 4.
Table 4 the results of the adhesion test of the stretched ultrathin films in examples 2 to 5
As can be seen from the test results in Table 4, the stretched ultrathin film prepared by the invention has better flexibility and adhesiveness, and the combination of the film prepared by the ultrathin film and the metal bracket is firmer.
(3) Observation by optical microscope and observation by fluorescence microscope
The above test was performed on the products obtained in examples 2 to 5 according to the test method in example 1, and the observation by an optical microscope shows that the ultra-thin films in examples 2 to 5 can form an oriented groove structure after being stretched and oriented, and the number of adherent growth of endothelial cells on the stretched ultra-thin film is greater than that of the unstretched ultra-thin film, which indicates that the film prepared by stretching the ultra-thin film will be more favorable for adherent growth of endothelial cells on the stent. Fluorescence microscopy observations show that the number of adherent growth of endothelial cells on the stretched ultrathin films of examples 2-5 is significantly greater, and that the cells have a tendency to orient along the groove structure of the film surface, indicating that a coating prepared with the stretched ultrathin film would be expected to guide the oriented growth of endothelial cells on the stent.
(4) Partial prothrombin time test
The APTT test was performed on different ultrathin film samples according to the test method in example 1, and the results are shown in FIG. 6, and FIG. 6 is an effect diagram of the APTT test in example 6; wherein PLA-PEG-1 is the stretched PLA-PEG ultrathin film in example 1, PLA-PEG-2 is the stretched PLA-PEG ultrathin film in example 2, PLA-PEG-3 is the stretched PLA-PEG ultrathin film in example 3, PCLA-PEG is the stretched PCLA-PEG ultrathin film in example 4, and PPDO-PEG is the stretched PPDO-PEG ultrathin film in example 5. Compared with 316L and PLA ultrathin films, the APTT results of the stretched copolymer ultrathin films in examples 2-5 are obviously prolonged, which shows that the PEG component in the ultrathin films can obviously prolong the coagulation time of the material, so that the material has good anticoagulation performance, and therefore, the coating film prepared by stretching the ultrathin film is expected to slow down the formation of thrombus in a stent.
The principles and embodiments of the present invention have been described herein with reference to specific examples, the description of which is intended only to aid in understanding the method of the invention and its core concept, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims. The scope of the patent protection is defined by the claims and may include other embodiments that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.
Claims (2)
1. A method for preparing a covered stent, comprising the steps of:
winding a degradable polymer ultrathin film on a vascular stent, wherein the degradable polymer ultrathin film is covered on the vascular stent through self-adhesion to obtain a covered vascular stent;
the preparation method of the degradable polymer ultrathin film comprises the following steps:
a) Dissolving a degradable high polymer material in a solvent to obtain a precursor solution;
the degradable macromolecule is a copolymer of degradable polyester and polyethylene glycol;
the degradable polyester and polyethylene glycol copolymer is one or more selected from polylactic acid, polyglycolide, polycaprolactone and polydioxanone, or at least two selected from polylactic acid, polyglycolide, polycaprolactone and polydioxanone;
the solvent is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, acetone, ethyl acetate, 1, 4-dioxane, benzene, toluene, N-dimethylformamide and N-methylpyrrolidone;
the concentration of the degradable high polymer material in the solvent is 1-1500 mg/mL;
b) Preparing a film from the precursor solution to obtain a base film;
the film forming mode is spin coating, film scraping method or tape casting method;
the spin coating operation is as follows: the precursor solution is dripped on a plane substrate, and the precursor solution is rotated for 5 to 2000s at 100 to 15000rpm and removed from the solvent at 5 to 100 ℃ to obtain a base film;
c) Stretching and orienting the base film to obtain a degradable coating film; the surface of the degradable coating film is provided with an oriented groove structure;
the conditions of the stretch orientation are: stretching orientation is carried out at a stretching speed of 1-100 cm/s, and the ambient temperature is 10-75 ℃;
the thickness of the degradable polymer ultrathin film is 0.01-1 mu m;
in the covered stent, the number of winding layers of the degradable polymer ultrathin film on the stent is 1-1000, and the total thickness is below 10 mu m.
2. The method according to claim 1, wherein in the step a), an anticoagulant/vascular endothelial growth-regulating drug or an active factor is further added during the addition;
the anticoagulant/vascular endothelial growth regulating medicine or active factor is one or more selected from heparin, hirudin, taxol, rapamycin, sirolimus and derivatives thereof, polypeptide and glycogen synthase kinase 3 beta inhibitor.
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