CN110917410B - A kind of cardiovascular stent coating based on double-layer heterogeneous structure and preparation method thereof - Google Patents

Abstract

The invention discloses a preparation method of a cardiovascular stent coating based on a double-layer heterogeneous structure, comprising: 1) constructing a drug coating containing an anti-proliferative drug on the cardiovascular stent; The water-soluble polymer is mixed and dissolved in a solvent and then sprayed on the drug coating, and then the porous coating is obtained by water immersion and dissolution; 3) The thiolated biomacromolecule solution containing the photoinitiator is covered on the surface of the porous coating, and the surface of the porous coating is irradiated with ultraviolet light. A heparinized modified porous coating is obtained, and finally, biological factors are loaded to obtain a cardiovascular stent coating. The invention also discloses the cardiovascular stent coating prepared by the above method. The above method is simple and efficient, greatly simplifies the preparation steps, and the prepared coating can enable the biological factor to be highly active loaded, thereby realizing the compounding of the growth factor and the drug, which can not only inhibit the intimal hyperplasia, but also promote the rapid repair of the endothelial layer. , to achieve better vascular tissue remodeling performance.

Description

A kind of cardiovascular stent coating based on double-layer heterogeneous structure and preparation method thereof

technical field

The invention relates to the field of biomedical materials, in particular to a cardiovascular stent coating based on a double-layer heterogeneous structure and a preparation method thereof.

Background technique

Cardiovascular diseases (CVD) are currently the number one killer of human life. According to a survey by the National Center for Cardiovascular Diseases, the number of CVD patients in China is currently as high as 290 million, among which coronary atherosclerotic heart disease (CHD) with a high mortality rate is about 11 million, which has become a major public health problem. Hygiene issue.

With the development of modern medical technology, drug-eluting stent (DES) implantation, which has the function of inhibiting neointimal hyperplasia, has become the gold standard for the treatment of cardiovascular diseases. However, with the widespread use of DES, adverse events such as late stent thrombosis (LST) have been continuously reported, which has raised concerns among researchers and patients about the late risk of DES. Clinical studies have shown that more than 50% of patients with late thrombosis have malposition and incomplete coverage. The delayed healing of vascular injury sites caused by DES is directly related to LST. sex. The researchers speculate that the antiproliferative drugs currently used not only inhibit the growth of smooth muscle cells, but also inhibit the growth of endothelial cells, thereby delaying the remodeling of the endothelial layer, which in turn affects endothelial function including anticoagulation. Therefore, it is of great significance to design the existing stent drug coating to suppress the intimal hyperplasia without affecting or even promoting the repair and functional reconstruction of the endothelial layer, which is of great significance for the reconstruction of normal vascular tissue.

In recent years, in the research field, researchers have adsorbed or immobilized biologically active macromolecules on the surface of the coating from the perspective of bionics, thereby realizing the function of promoting the rapid remodeling of the endothelial layer. For example, by covalently immobilizing an active polypeptide containing a specific affinity sequence REDV on an inert coating, the adhesion and proliferation ability of vascular endothelial cells on its surface is much greater than that of smooth muscle cells, thereby achieving rapid remodeling of the endothelial layer. The immobilization of antibody anti-34, vascular endothelial cell growth factor VEGF, etc. on the surface of the material by layer-by-layer self-assembly can significantly improve the affinity of the material with endothelial cells and regulate the growth of endothelial cells, so as to achieve the same effect on the surface of the implant. Rapid remodeling of the endothelial layer, reducing the incidence of adverse events of restenosis and thrombosis.

Although bioactive molecules have been widely developed and utilized in the research field, showing extraordinary prospects, however, the design of bioactive functional coatings that are truly applied in clinical treatment is rarely reported. Among them, the antibody-modified coating represented by the Genous stent developed by OrbusNeich is the only bioactive coated stent at present. However, in the actual clinical comparative study, the Genous stent modified with antibody anti-CD34 did not show the expected superior effect of compounding compared with the traditional drug-eluting stent. There are many possible reasons. On the one hand, the process of sterilization and storage, which is indispensable in the preparation process, will cause irreversible damage to the bioactive molecules, making the bioactive molecules partially or completely invalid, thus greatly weakening the bioactive molecules. On the other hand, the loss of blood vessels caused by stents in the early stage of implantation will initiate the body's self-repair mechanism, so the use of early anti-proliferative drugs is indispensable.

To sum up, the traditional drug-eluting stent coating delays or even hinders the endothelial layer remodeling of blood vessels, thereby increasing the risk of late thrombosis; bioactive molecules with specificity of endothelial cells can achieve the purpose of accelerating endothelial layer repair, However, how to deal with the destruction of bioactive molecules during sterilization and storage during scaffold preparation is still challenging. More importantly, the use of anti-proliferative drugs in stent coating is unavoidable because the stent implantation process inevitably causes the loss of blood vessels, thereby stimulating the self-healing mechanism of blood vessels.

Therefore, a stent coating is designed to realize the combination of anti-proliferative drugs and bioactive functional molecules, which can satisfy the sustained release of anti-proliferative drugs on the one hand, and maintain the biological activity of bioactive molecules on the other hand. It is of great significance to reduce complications and improve the quality of life of patients.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a cardiovascular stent coating based on a double-layer heterogeneous structure to promote endothelial layer repair and a preparation method thereof, which realizes the highly active loading of biological factors, and further utilizes the synergistic effect of biological factors and drugs to achieve It can quickly promote the repair of vascular endothelial layer while inhibiting excessive intimal hyperplasia.

In order to achieve the above purpose of the invention, the present invention provides a method for preparing a cardiovascular stent coating based on a double-layer heterogeneous structure, comprising the following steps:

(1) Constructing a drug coating containing anti-proliferative drugs on a cardiovascular stent;

(2) mixing the double bond-terminated polymer and the water-soluble polymer, dissolving it in a solvent, spraying on the drug coating, and then immersing and dissolving with water to obtain a porous coating;

(3) Covering the surface of the porous coating with a thiolated biomacromolecule solution containing a photoinitiator, irradiating with ultraviolet light to obtain a porous coating modified by biomacromolecules, and finally loading biological factors to obtain a cardiovascular stent coating.

The cardiovascular stent coating provided by the invention has a double-layer heterogeneous structure, the bottom layer of the coating is a degradable dense coating containing anti-proliferative drugs, and the top layer is a biodegradable porous coating modified by biological macromolecules. The biological factors are completed before the stent implantation operation, thereby overcoming the problem that the biological factors are difficult to preserve in the existing coating, and realizing the effective combination of biological factors and anti-proliferative drugs. The prepared stent can not only inhibit excessive intimal hyperplasia, but also It can also quickly promote the repair of the vascular endothelial layer.

In addition, since growth factors have strong specific interactions with some biomacromolecules (such as heparin, hyaluronic acid, etc.), how to realize the biomacromolecule modification of porous coatings is crucial. In the previous literature, the self-assembly method was used to immobilize biomacromolecules on the surface of the substrate. However, this method is cumbersome and difficult to prepare efficiently and stably in industrial preparation. The present invention first finds that: firstly, the biomacromolecules are modified with sulfhydryl groups to obtain a solution of sulfhydrylated biomacromolecules, and then the photo-click reaction between the sulfhydryl groups and double bonds can be used to covalently modify the biomacromolecules into the porous coating in one step. The preparation steps are greatly simplified, and the industrialized efficient and stable preparation can be realized.

The preparation method of the above-mentioned double-layer heterogeneous structure-based cardiovascular stent coating includes three steps: drug coating construction, porous coating construction, and porous coating biomacromolecule modification.

(1) In step (1), the construction of drug coating:

The drug coating is obtained by dissolving an anti-proliferative drug and a degradable polymer in a solvent and then spraying it on a cardiovascular stent by ultrasonic atomization.

The degradable polymer is one of poly-L-lactic acid (PLLA), poly-racemic-lactic acid (PDLLA), poly-lactic-co-glycolic acid (PLGA) or poly-caprolactone (PCL); number-average molecular weight The number average molecular weight is preferably 50,000-150,000, taking into account the degradation time of the coating.

Preferably, the degradable polymer is PLGA with a lactic acid (LA) content of 50%-75% in the copolymer. This is because the degradation rate of PLGA is related to the ratio of its internal copolymer, and the degradation effect is better in this ratio range. .

The anti-proliferative drugs include paclitaxel or its derivatives, rapamycin or its derivatives. The dosage of the anti-proliferative drug is 1-15 μg/mm stent, preferably 3-10 μg/mm stent.

The solvent includes one or more of acetone, ethyl acetate, dichloromethane, chloroform and tetrahydrofuran, preferably one or more of acetone, ethyl acetate and chloroform.

Preferably, the drug coating is obtained by spraying on the cardiovascular stent by means of ultrasonic atomization spraying. The thickness of the drug coating is 5-20 μm, preferably 5-10 μm.

(2) In step (2), the construction of porous coating:

The double bond-terminated polymer is methacrylate group-terminated poly-L-lactic acid (PLLA), poly(lactic acid) (PDLLA), poly(lactic-co-glycolic acid) (PLGA) or polycaprolactone (PCL). ), the number-average molecular weight is 10,000-300,000, and the number-average molecular weight is preferably 50,000-150,000 in consideration of the degradation time of the coating.

Since the degradation rate of PLGA is related to its internal copolymer ratio, the double bond-terminated polymer is preferably PLGA with a methacrylate group-terminated lactic acid (LA) content of 50%-75%.

The construction method of the porous coating is a water erosion method, wherein the water-soluble polymer includes polyethylene glycol or polyvinyl pyrrolidone, and the number average molecular weight is 10,000-200,000. Considering that the water solubility of the water-soluble polymer is closely related to the molecular weight, the number average molecular weight is preferably 10,000 to 80,000.

The selected solvent includes one or more of acetone, ethyl acetate, dichloromethane, chloroform, and tetrahydrofuran, and considering the mutual solubility of the two polymers, it is preferably dichloromethane or chloroform.

The water-soluble polymer accounts for 20%-80% of the total polymer mass fraction. However, when the ratio of the dissolution phase is too low, the uniformity of the porous structure obtained by phase separation is poor; and when the ratio of the dissolution phase is too high, the stability of the porous coating will be affected; therefore, considering the uniformity of the porous structure and the coating For the stability of the layer, preferably the water-soluble polymer accounts for 40%-60% of the total polymer mass fraction.

Preferably, it is sprayed on the drug coating by means of ultrasonic atomization spraying. The dissolution time of the water is 4-6 minutes/time, and the dissolution times are 2-3 times. The thickness of the porous coating is 2-20 μm, preferably 5-10 μm.

(3) In step (3), the porous coating biomacromolecule is modified:

The biological macromolecule is heparin or hyaluronic acid, and the molecular weight is 0.2-100,000.

The photoinitiator is photoinitiator I2959, the concentration of the photoinitiator is 250-350 ppm, and the concentration of the thiolated biomacromolecule solution is 4-6 mg/ml.

The conditions of the ultraviolet light irradiation are: irradiating in a 365 nm LED ultraviolet light curing apparatus for 1-10 minutes, and the ultraviolet light intensity is 50-200 mW/cm ² .

The growth factor biological factors are rapidly adsorbed on the porous coating through capillary action to prepare the cardiovascular stent coating. The total concentration of the biological factors is 20-200 μg/ml, and the biological factors include human vascular endothelial growth factor (VEGF) or/and human hepatocyte growth factor (HGF). The biological factor loading on the cardiovascular stent coating is 10-1000 ng/cm ² .

Since both the growth factors VEGF and HGF have the specific growth-promoting ability of endothelial cells, the growth of smooth muscle cells on the composite coating is significantly inhibited by using the active loading mode of the present invention, while endothelial cells can better maintain their increase. Furthermore, in practical applications, it is expected to achieve anti-intimal hyperplasia while promoting the remodeling of the vascular endothelial layer, thereby reducing the risk of late thrombosis.

The present invention also provides a double-layer heterogeneous structure-based cardiovascular stent coating prepared by the above preparation method.

Compared with the prior art, the present invention has the following beneficial effects:

(1) The present invention solves the problems that the single-layer drug-coated stent has the risk of poor vascular healing, and the activity of biological factors is seriously affected by many processes such as coating preparation, sterilization, and storage. The base layer of the coating of the present invention is a drug-loaded coating, which realizes the sustained release of anti-proliferative drugs. By further constructing a porous coating with growth factor affinity on the drug-loaded coating, it is only necessary to Real-time adsorption of growth factor biological factors before surgical implantation, so that biological factors can be loaded with high activity, so as to achieve the compounding of growth factors and drugs, which can not only inhibit intimal hyperplasia, but also promote the rapid repair of endothelial layer and achieve better blood vessels. Tissue refactoring performance.

(2) The method of the present invention firstly modifies the biomacromolecules with sulfhydryl groups to obtain a solution of sulfhydrylated biomacromolecules, and then utilizes the light click reaction between the sulfhydryl groups and the double bonds to efficiently covalently modify the biomacromolecules into the porous coating in one step. , the preparation steps are greatly simplified, and the industrialized, efficient and stable preparation of the above-mentioned cardiovascular stent coating can be realized.

Description of drawings

FIG. 1 is an apparent view (a) and a micrograph (b) of the coated stent without growth factor loaded according to the present invention;

2 is a fluorescence micrograph and a three-dimensional reconstruction image of the coating after the fluorescently labeled growth factor is loaded in the present invention;

Figure 3 is a comparison diagram of the co-culture proliferation behavior of endothelial cells and smooth muscle cells in Example 1 before (a) and after loading with VEGF (b);

FIG. 4 is a graph showing the comparison of the proliferation density of endothelial cells and smooth muscle cells before loading with VEGF (-VEGF) and after loading with VEGF (+VEGF) in Example 1. FIG.

Detailed ways

It should be pointed out that the coating of the present invention can be used for stents of various materials, such as metal stents and degradable stents. For the convenience of description, in the following specific examples, the present invention adopts poly-L-lactic acid (PLLA) as the model substrate Coatings are constructed, but actual stent materials include, but are not limited to, those in the Examples.

The preparation methods of thiolated biomacromolecules described in the following examples are obtained based on literature (references: Wang, L.M.; Chang, H.; Zhang, H.; Ren, K.F.; Li, H.; Hu, M.; Li , B.C.; Martins, M.C.L.; Barbosa, M.A.; Ji, J., Dynamic stiffness of polyelectrolyte multilayer films based on disulfide bonds for in situ control of cell adhesion. JMater Chem B 2015,3(38),7546-7553.), with Taking thiolated heparin as an example, the detailed preparation method is as follows: Dissolve 0.2 g of heparin sodium (average molecular weight: 12000) in acetic acid buffer with pH=5.5, add 0.42 g of 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide (EDC), stir at room temperature for 1 hour, add 0.25g N-hydroxysuccinimide (NHS) and 0.49g cystamine dihydrochloride, stir at room temperature for 24 hours, then remove unreacted by dialysis of cystamine dihydrochloride and catalyst EDC/NHS. The obtained solution was added with 0.34g dithiothreitol (DTT), and the reaction was stirred at room temperature for 6 hours. Then, the residual DTT and the small molecule cysteine obtained by the reaction were removed by dialysis, and the remaining solution was freeze-dried to prepare thiolated heparin. .

Example 1: VEGF/rapamycin co-loaded stent coating

(1) Preparation of rapamycin/PDLLA drug layer: PDLLA with a number average molecular weight of 100,000 is used as the degradable coating material, rapamycin is used as an anti-proliferative drug, and chloroform is used as a solvent, which is prepared by ultrasonic atomization spraying The drug-loaded base layer has a drug coating thickness of 10 μm, and when the base is a stent, the rapamycin content is 6 μg/mm.

(2) Preparation of heparinized PDLLA porous coating: PDLLA with a double bond-terminated number average molecular weight of 100,000 was used as the coating material, and polyvinylpyrrolidone (PVP) with a weight average molecular weight of 40,000 was used as the corrosion phase. The mass fraction of the corrosion phase 55%, using chloroform as solvent, using ultrasonic spraying method to coat the blend on the drug-carrying layer of the substrate, and obtain a porous coating with a thickness of 5 μm by etching with sterile ultrapure water. Subsequently, the surface of the coating was covered with a thiolated heparin aqueous solution (concentration 5 mg/ml) containing 300 ppm of photoinitiator I2959, and an LED 365 nm light source UV lamp was used to irradiate for 5 minutes under the light intensity of 100 mW/cm ^2. After cleaning with ultrapure water Vacuum drying to obtain heparin-modified bilayer heterogeneous structure coating.

(3) VEGF loading: The coating was immersed in a sterile aqueous solution of VEGF with a concentration of 50 μg/ml, fully soaked for 2 minutes, and then taken out. After washing with sterile water, a VEGF/rapamycin co-loaded coating was obtained. The loading was 560±40 ng/cm ² .

Fig. 1(a) is an apparent view of the coated scaffold without growth factor loaded in step (2), and Fig. 1(b) is a microscopic view of the coated scaffold without growth factor loaded in step (3). picture.

FIG. 2 is a fluorescence micrograph and a three-dimensional reconstruction image of the coating after the growth factor is loaded with fluorescently labeled growth factors. It can be seen from FIG. 2 that the adsorbed biological factors are evenly distributed in the coating.

Figures 3 and 4 are graphs showing the comparison of the proliferation behavior of endothelial cells and smooth muscle cells before and after loading with VEGF. It can be seen from the figures that after using the active loading growth factor of the present invention, the growth of smooth muscle cells on the composite coating is significantly inhibited, while endothelial cells can be more maintain its growth well.

Example 2: VEGF/paclitaxel co-loaded stent coating

(1) Preparation of paclitaxel/PLGA drug layer: PLGA with a number average molecular weight of 100,000 (LA:GA=75:25) was used as the degradable coating material, paclitaxel was used as an anti-proliferative drug, and chloroform was used as a solvent. The drug base layer, the drug coating thickness is 10 μm, and the drug loading is 5 μg/mm.

(2) Preparation of hyaluronic acid-modified PLGA porous coating: PLGA with a double bond-terminated number average molecular weight of 100,000 was used as the coating material, and polyvinylpyrrolidone (PVP) with a weight average molecular weight of 40,000 was used as the corrosion phase. The mass fraction is 60%, chloroform is used as the solvent, the blend is coated on the substrate drug-carrying layer by ultrasonic spraying method, and a porous coating with a thickness of 5 μm is obtained by etching with sterile ultrapure water. Subsequently, the coating surface was covered with a thiolated hyaluronic acid aqueous solution (molecular weight 50,000, concentration 5mg/ml) containing 300ppm of photoinitiator I2959, and irradiated for 5 minutes under an LED 365nm light source UV lamp with a light intensity of 80mW/cm ² , washed with ultrapure water and dried in vacuum to obtain a heparin-modified double-layer heterogeneous structure coating.

(3) VEGF loading: The coating was immersed in a sterile aqueous solution of VEGF with a concentration of 100 μg/ml, fully soaked for 2 minutes, and then taken out. After washing with sterile water, a VEGF/paclitaxel co-loaded coating was obtained. The loading amount of VEGF was 860±65ng/cm ² .

Through the combined action of VEGF and paclitaxel, the coating significantly inhibited the proliferation of smooth muscle cells and specifically reduced the effect of paclitaxel on endothelial cells, which were 15 times denser than smooth muscle cells.

Example 3: VEGF/zotarolimus co-loaded stent coating

(1) Preparation of zotarolimus/PDLLA drug layer: PDLLA with a number average molecular weight of 150,000 was used as a degradable coating material, paclitaxel was used as an anti-proliferative drug, and chloroform was used as a solvent, and the drug-loaded base layer was prepared by ultrasonic spraying. The layer thickness was 5 μm, and the drug loading was 5 μg/mm.

(2) Preparation of heparinized PLGA porous coating: PDLLA with a double bond-terminated number average molecular weight of 100,000 was used as the coating material, polyethylene glycol (PEG) with a weight average molecular weight of 10,000 was used as the erosion phase, and the mass fraction of the erosion phase was 50%, chloroform was used as a solvent, the blend was coated on the substrate drug-carrying layer by ultrasonic spraying method, and a porous coating with a thickness of 5 μm was obtained by etching with sterile ultrapure water. Subsequently, the surface of the coating was covered with a thiolated heparin solution (concentration 5 mg/ml) containing 300 ppm of photoinitiator I2959, and an LED 365 nm light source UV lamp was used to irradiate for 5 minutes at a light intensity of 100 mW/cm ^2. After cleaning with ultrapure water Vacuum drying to obtain heparin-modified bilayer heterogeneous structure coating.

(3) VEGF loading: The coating was immersed in a sterile aqueous solution of VEGF with a concentration of 50 μg/ml, fully soaked for 2 minutes, and then taken out. After washing with sterile water, a VEGF/paclitaxel co-loading coating was obtained. The loading amount of VEGF was 520±45ng/cm ² .

Through the combined action of VEGF and zotarolimus, the coating significantly inhibited the proliferation of smooth muscle cells and specifically reduced the effect of paclitaxel on endothelial cells, which were 20 times denser than smooth muscle cells.

Example 4: HGF/rapamycin co-loaded stent coating

(1) Preparation of rapamycin/PDLLA drug layer: PDLLA with a number average molecular weight of 150,000 was used as the degradable coating material, rapamycin was used as an anti-proliferative drug, and chloroform was used as a solvent, and the drug-loaded base layer was prepared by ultrasonic spraying , the drug coating thickness is 5 μm, and the drug loading is 4 μg/mm.

(2) Preparation of hyaluronic acid-modified PDLLA porous coating: PDLLA with a double bond-terminated number average molecular weight of 150,000 was used as the coating material, and polyvinylpyrrolidone (PVP) with a weight average molecular weight of 40,000 was used as the corrosion phase. The mass fraction is 55%, chloroform is used as a solvent, the blend is coated on the drug-loaded layer of the substrate by ultrasonic spraying, and a porous coating with a thickness of 5 μm is obtained by etching with sterile ultrapure water. Subsequently, the surface of the coating was covered with a thiolated hyaluronic acid solution (molecular weight 100,000, concentration 5 mg/ml) containing 300 ppm of photoinitiator I2959, and irradiated for 5 minutes with an LED 365 nm light source UV lamp with a light intensity of 100 mW/cm ² , washed with ultrapure water and dried in vacuum to obtain a heparin-modified double-layer heterogeneous structure coating.

(3) HGF loading: The coating was immersed in a sterile aqueous solution of HGF with a concentration of 100 μg/ml, fully soaked for 1 minute, and then taken out. After washing with sterile water, a VEGF/rapamycin co-loaded coating was obtained. The loading was 760±55 ng/cm ² .

Through the combined action of HGF and rapamycin, the coating significantly inhibited the proliferation of smooth muscle cells and specifically reduced the effect of paclitaxel on endothelial cells, which were 12 times denser than smooth muscle cells.

Example 5: HGF/zotarolimus co-loaded stent coating

(1) Preparation of zotarolimus/PLLA drug layer: PLLA with a number average molecular weight of 80,000 was used as the degradable coating material, zotarolimus was used as an anti-proliferative drug, and chloroform was used as a solvent, and the drug-loaded base layer was prepared by ultrasonic spraying , the drug coating thickness is 5 μm, and the drug loading is 4 μg/mm.

(2) Preparation of heparinized PDLLA porous coating: PDLLA with a double bond-terminated number average molecular weight of 100,000 was used as the coating material, and polyvinylpyrrolidone (PVP) with a weight average molecular weight of 40,000 was used as the corrosion phase. The mass fraction of the corrosion phase 55%, chloroform was used as solvent, the blend was coated on the substrate drug-carrying layer by ultrasonic spraying method, and a porous coating with a thickness of 5 μm was obtained by etching with sterile ultrapure water. Subsequently, the coating surface was covered with a thiolated heparin aqueous solution (concentration 5 mg/ml) containing 300 ppm of photoinitiator I2959, and irradiated with an LED 365 nm light source ultraviolet lamp with a light intensity of 100 mW/cm ² for 5 minutes, and after cleaning with ultrapure water Vacuum drying to obtain heparin-modified bilayer heterogeneous structure coating.

(3) HGF loading: The coating was immersed in a sterile aqueous solution of HGF with a concentration of 50 μg/ml, fully soaked for 1 minute, and then taken out. After washing with sterile water, a VEGF/rapamycin co-loaded coating was obtained. The loading was 580±60 ng/cm ² .

Through the combined action of HGF and zotarolimus, the coating significantly inhibited the proliferation of smooth muscle cells and specifically reduced the effect of paclitaxel on endothelial cells, which were 14 times denser than smooth muscle cells.

Claims (9)

1. a preparation method based on a double-layer heterogeneous structure cardiovascular stent coating, comprising the following steps: (1) Constructing a drug coating containing anti-proliferative drugs on a cardiovascular stent; (2) the double-bond-terminated polymer and the water-soluble polymer are mixed and dissolved in a solvent, sprayed on the drug coating, and then immersed and eroded with water to obtain a porous coating; the double-bond-terminated is a methacrylate-based seal end; (3) immersing the thiolated biomacromolecule solution containing the photoinitiator on the surface of the porous coating, irradiating with ultraviolet light to obtain the porous coating modified by the biomacromolecule, and finally loading biological factors to obtain the cardiovascular stent coating. 2 . The method for preparing a cardiovascular stent coating based on a double-layer heterogeneous structure according to claim 1 , wherein in step (1), the drug coating is dissolved in a solvent by using an anti-proliferative drug and a polymer. 3 . After ultrasonic atomization spraying on the cardiovascular stent to obtain. 3. The method for preparing a cardiovascular stent coating based on a double-layer heterogeneous structure according to claim 1 or 2, wherein the anti-proliferative drug comprises paclitaxel or its derivatives, rapamycin or its derivative. 4. The method for preparing a cardiovascular stent coating based on a double-layer heterogeneous structure according to claim 1, wherein in step (2), the water-soluble polymer is polyethylene glycol or polyvinyl Pyrrolidone, the number average molecular weight is 1-200,000. 5 . The method for preparing a cardiovascular stent coating based on a double-layer heterogeneous structure according to claim 1 , wherein in step (2), the water-soluble polymer accounts for 20% of the total polymer mass fraction. 6 . -80%. 6. The method for preparing a cardiovascular stent coating based on a double-layer heterogeneous structure according to claim 1, wherein in step (3), the photoinitiator is photoinitiator I2959, and the photoinitiator is I2959. The concentration of the initiator is 250-350 ppm. 7. The method for preparing a cardiovascular stent coating based on a double-layer heterogeneous structure according to claim 1, wherein in step (3), the biological macromolecule is heparin or hyaluronic acid, and the molecular weight is 0.2 -100,000, the concentration of thiolated biomacromolecule solution is 4-6mg/ml. 8. The method for preparing a cardiovascular stent coating based on a double-layer heterogeneous structure according to claim 1, wherein in step (3), the biological factor comprises human vascular endothelial cell growth factor or/and Human hepatocyte growth factor. 9 . A cardiovascular stent coating based on a double-layer heterogeneous structure, characterized in that, it is prepared by the preparation method according to any one of claims 1 to 8 .

Images