Thoracico-abdominal aorta covered stent and preparation method thereof

Abstract

The invention discloses a thoracoabdominal aorta covered stent and a preparation method thereof, the preparation method comprises the following steps: designing a stent structure, preparing a drug-loaded nano material, assembling a surface coating, preparing mesoporous silica nanoparticles (MSNs) by a sol-gel method, carrying out amination modification, loading an antibacterial agent ciprofloxacin and an anticoagulant heparin, and preparing the thoracoabdominal aorta covered stent. The preparation method comprises the following steps: carrying out ultrasonic treatment on the surface of a stent to form multifunctional drug-loaded nanoparticles, carrying out plasma cleaning on the stent, sequentially dipping the stent in a chitosan solution, a drug-loaded MSNs dispersion liquid and a hyaluronic acid solution, circularly constructing a multi-layer structure, enhancing the stability of the coating through EDC / NHS chemical crosslinking, and finally forming a composite nano-coating with antibacterial and anticoagulant functions on the surface of the stent. The biocompatibility and the clinical application safety of the stent are improved.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and in particular to a thoracoabdominal aortic endovascular stent and its preparation method. Background Technology

[0002] Thoracic and abdominal aortic diseases, including thoracic aortic dissection and abdominal aortic aneurysm, are among the most common acute and critical illnesses in vascular surgery, resembling a ticking time bomb. In recent years, with continuous advancements in medical technology, the treatment of aortic diseases has gradually transitioned from traditional open surgery to endovascular repair, achieving a technological shift from "major trauma" to "minimally invasive." Endovascular grafts are increasingly used in the treatment of aortic dissection and thoracic and abdominal aortic aneurysms. However, due to the complexity of the aorta's anatomy, stents used in endovascular treatment often exhibit significant gaps due to poor adhesion between stents and between the stent and the aortic wall, easily leading to endoleaks. Furthermore, the anti-infective properties and biocompatibility of endovascular stent grafts directly affect the incidence of complications. Nanoparticles, due to their small size and large specific surface area, exhibit excellent antibacterial properties and can more easily penetrate biofilms to interact with fungi, leading to their widespread application in the field of antifungal technology in recent years.

[0003] While coatings formed by nanoparticles on the surface of alloy scaffolds can improve the anti-infection properties and biocompatibility of covered scaffolds, the following drawbacks also exist: (1) It is difficult to achieve both physical barrier and chemical sterilization: In general, in order to achieve the best antibacterial effect, the nanoparticle coating needs to form an effective physical barrier to prevent bacteria from attaching, while also releasing substances with bactericidal effect. However, in practical applications, it is often difficult to achieve both at the same time.

[0004] (2) Long-term stability issues: The long-term stability and effectiveness of the nanocoating in vivo is an important consideration. Over time, the nanoparticles may gradually detach from the scaffold surface or become inactive, affecting their long-term antibacterial properties. Summary of the Invention

[0005] The purpose of this invention is to provide a thoracoabdominal aortic endovascular stent and its preparation method, so as to solve the problems of difficulty in simultaneously achieving physical barrier and chemical sterilization of the nano-coating on the surface of the above-mentioned alloy stent and low long-term stability.

[0006] To achieve the above objectives, the first aspect of the present invention provides a method for preparing a thoracoabdominal aortic endovascular stent graft, comprising the following steps: S1: Design the support structure; S2: Preparation of drug-loaded nanomaterials S21: Using the sol-gel method, the template agent is dissolved in a mixture of deionized water and ammonia water. After thorough stirring, tetraethyl orthosilicate is added and the reaction is continued. After the reaction is completed, the precipitate is collected by centrifugation, the template agent is removed by washing, and the precipitate is dried to obtain mesoporous silica nanoparticles. S22: Mesoporous silica nanoparticles were dispersed in ethanol, and then 3-aminopropyltriethoxysilane was added and stirred. After the reaction was completed, the nanoparticles were centrifuged, washed and dried to obtain amino-functionalized mesoporous silica nanoparticles. S23: Dissolve the antibacterial agent in ethanol, then add amino-functionalized mesoporous silica nanoparticles, stir the reaction, and after the reaction is complete, wash and dry to obtain mesoporous silica nanoparticles with antibacterial effect. S24: Dissolve the anticoagulant in deionized water, then add mesoporous silica nanoparticles with antibacterial properties, stir the reaction, and after the reaction is complete, wash and dry to obtain drug-loaded mesoporous silica nanoparticles. S3: Assembly of the covered stent After plasma cleaning and activation, the scaffold structure is first immersed in a chitosan solution to form a base layer, and then alternately immersed in a drug-loaded mesoporous silica nanoparticle dispersion and a hyaluronic acid solution. After immersion, an EDC / NHS chemical crosslinking is used to form a nano-coating on the surface of the scaffold structure, and finally a membrane scaffold is obtained.

[0007] In microbiological studies of aortic stent graft infection, common pathogens include Staphylococcus (30.1%), Streptococcus (14.8%), and fungi (9.2%), with an incidence rate ranging from 0.2% to 5.0%. Traditional graft materials such as polytetrafluoroethylene (PTFE) or polyurethane lack active antibacterial capabilities and are prone to bacterial biofilm formation. To enhance the graft's resistance to infection and biocompatibility, this invention employs nanocoating technology, reducing the risk of infection through a dual mechanism of physical barrier and chemical sterilization.

[0008] Preferably, in step S1, the stent structure includes a main stent and a movable stent. The main stent is divided into a dual-lumen shunt structure by a vertical partition, wherein the large chamber is connected to the aorta, and a multi-modular shunt structure is embedded in the small chamber. The irregularly shaped connecting end of the movable stent is spliced ​​into multiple parts and forms a sealed interface with the multi-modular shunt structure. The stent structure is made of corrugated shape memory alloy.

[0009] The main body of the support of this invention adopts a corrugated shape memory alloy skeleton and a film-coated composite structure, combined with barb anchoring (micro barbs are integrated at the troughs of the corrugated shape memory alloy skeleton, the barbs are designed with a reverse tilt angle of 15°~45°, the material is nickel-titanium alloy (NiTiNOL), and are integrally laser-cut with the main body of the support, and have a hook interlocking design (the end is designed as "dovetail hooks", the material is super-elastic nickel-titanium alloy) to achieve high compliance fixation.

[0010] The scaffold structure in this invention is just one of many scaffold structures. The main inventive point of this invention is to prepare a nano-coating on the surface of the scaffold structure. The preparation process of the nano-coating is not limited to the above-mentioned scaffold structure, but is also applicable to other scaffold structures to form the same nano-coating on their surface and achieve the same technical effect.

[0011] Preferably, in step S21, the template agent is hexadecyltrimethylammonium bromide, and the addition ratio of hexadecyltrimethylammonium bromide, deionized water, ammonia and tetraethyl orthosilicate is 3~8g:150~250mL:1~3mL:15~25mL.

[0012] Preferably, in step S22, the mass-to-volume ratio of mesoporous silica nanoparticles to 3-aminopropyltriethoxysilane is 450~550 mg: 10 mL.

[0013] In step S22, in order to enhance the drug loading capacity of MSNs, their surface needs to be functionalized with amino groups, so that amino groups are grafted onto the surface of MSNs pores.

[0014] Preferably, in step S23, the antibacterial agent is ciprofloxacin, and the mass ratio of ciprofloxacin to amino-functionalized mesoporous silica nanoparticles is 25~35:100.

[0015] In step S23, since ciprofloxacin is hydrophobic, it can be loaded into the pores of MSNs through physical adsorption.

[0016] Preferably, in step S24, the anticoagulant is heparin, and the addition ratio of heparin and mesoporous silica nanoparticles with antibacterial activity is 150~250 IU: 100 mg.

[0017] In step S24, heparin is further adsorbed onto the surface of MSNs and within the residual pore space through electrostatic binding.

[0018] Preferably, in step S3, the parameters for plasma cleaning are: The parameters for plasma cleaning are: power 150~250W, processing time 5~30 minutes; The preparation process of chitosan solution is as follows: dissolve chitosan in 3% acetic acid solution to form a chitosan solution with a concentration of 3-8%; Preparation of drug-loaded mesoporous silica nanoparticle dispersion: Disperse drug-loaded mesoporous silica nanoparticles in PBS buffer at a concentration of 10 mg / ml; Preparation process of hyaluronic acid solution: Hyaluronic acid is added to a heated solvent to dissolve until a transparent solution is formed. The pH value is adjusted to 6-7, filtered and sterilized to obtain a 10mg / mL hyaluronic acid solution.

[0019] Preferably, in step S3, the specific process of forming a nano-coating on the surface of the scaffold structure using EDC / NHS chemical crosslinking is as follows: (1) After the last layer of hyaluronic acid solution is impregnated, the scaffold structure is removed and gently rinsed three times with 0.01mol / L pH=7.4 PBS solution to remove unbound hyaluronic acid; (2) Immediately afterwards, the scaffold structure was immersed in freshly prepared EDC / NHS crosslinking solution and reacted at 4°C in the dark for 12-24 hours. The crosslinking solution formula was: 50 mmol / L pH=5.5 MES buffer, 0.05 mol / L EDC·HCl, and 0.02 mol / L NHS. (3) After the reaction is completed, rinse three times each with 0.1 mol / L pH=7.4 Na2HPO4 and deionized water to terminate the reaction and remove residual crosslinking agent; (4) Finally, the film-coated scaffold is dried to obtain the final product.

[0020] Preferably, the drying in step (4) can be done by blowing with nitrogen or by vacuum drying.

[0021] A second aspect of the present invention provides a thoracoabdominal aortic endovascular stent graft, which is prepared by the above-described method. The thoracoabdominal aortic endovascular stent graft includes a stent structure and a nano-coating, wherein the nano-coating is disposed on the surface of the stent structure.

[0022] Therefore, the thoracic and abdominal aortic endovascular stent with the above-described structure and its preparation method have the following beneficial effects: (1) This invention incorporates antibacterial agents (such as ciprofloxacin) into mesoporous silica nanoparticles (MSNs), which not only achieves slow drug release but also provides long-term inhibition of bacterial growth. The large specific surface area and ordered pore structure of MSNs provide an ideal carrier platform for drugs, enabling continuous drug release at specific sites and avoiding the toxic side effects of high-concentration antibiotics in certain areas. In addition, MSNs themselves have a certain physical barrier function, which can prevent bacteria from directly adhering to the scaffold surface to form a biofilm, thereby effectively preventing infection. This dual-pronged strategy of the present invention solves the problem that traditional coatings cannot simultaneously achieve both physical barrier and chemical sterilization.

[0023] (2) This invention also introduces an anticoagulant (such as heparin) into MSNs, which can significantly improve their biocompatibility without changing the basic properties of the stent material. Heparin, as a potent anticoagulant, can effectively reduce the coagulation reaction caused by blood contact with foreign bodies, reducing the risk of thrombosis. This invention not only helps maintain vascular patency and prevent restenosis or occlusion caused by thrombosis, but also reduces the burden on patients using anticoagulant drugs after surgery. In addition, heparin also has a certain anti-inflammatory effect, which helps to alleviate the inflammatory response that may occur after implantation, further improving the biocompatibility of the stent.

[0024] (3) This invention optimizes the stent structure. The main stent is made of corrugated shape memory alloy and is divided into a dual-lumen shunt structure. This design greatly enhances the flexibility and compliance of the stent. The corrugated design gives the stent better elasticity, enabling it to adapt to complex anatomical changes while reducing pressure on surrounding tissues. The dual-lumen shunt structure allows for adjustment of blood flow direction and velocity as needed, protecting vital organs from abnormal blood flow. The embedded multi-modal lumen structure can be flexibly adjusted according to the number of affected vascular branches, ensuring a tight fit between the stent and the vessel wall, reducing the possibility of blood leakage, and improving the success rate of the surgery.

[0025] (4) In this invention, after alternating impregnation of the scaffold structure, an EDC / NHS chemical crosslinking technique is used to construct a nano-coating on the surface of the scaffold structure. This is a key step in enhancing the stability of the coating. EDC / NHS crosslinking not only promotes the formation of covalent bonds between amino and carboxyl groups, but also increases the connection strength between the layers within the coating, preventing nanoparticles from detaching from the scaffold surface or becoming inactive. This crosslinking method is applicable to various types of intermolecular crosslinking, and is simple to operate under mild conditions, without affecting drug activity. Therefore, the coating treated with EDC / NHS chemical crosslinking has higher mechanical stability and long-lasting antibacterial properties, and can maintain its effectiveness in the in vivo environment for a longer period of time.

[0026] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0027] Figure 1 A schematic diagram of the stent structure of a branch of the iliac artery; Figure 2 A TEM image for MSNs; Figure 3 FTIR image of the covered stent; Figure 4 The results show the test effects of the coating on the biofilm formation inhibitory effect of the membrane-covered scaffold. Figure 5 The results of the antibacterial test for the covered scaffold; Figure 6 Results of inflammatory factor testing for covered stents; Figure 7 The results of tissue staining tests on the covered scaffold; In the diagram: 1. Lumen of the common iliac artery; 2. Stent body one; 3. Stent body two; 4. Wall of the common iliac artery; 5. Stent body three; 6. Lumen of the right iliac artery segment. Detailed Implementation

[0028] The present invention will be further described below. It should be noted that this embodiment is based on the present technical solution and provides detailed implementation methods and specific operation processes, but the present invention is not limited to this embodiment.

[0029] Example 1

[0030] A method for preparing a thoracoabdominal aortic endovascular stent graft includes the following steps: S1: Design of support structure The stent structure includes a main stent and a movable stent. The main stent is divided into a dual-lumen shunt structure by a vertical partition. The large chamber is connected to the aorta, and the small chamber is embedded with a multi-modular shunt structure. The irregularly shaped connecting end of the movable stent is spliced ​​into multiple parts and forms a sealed interface with the multi-modular shunt structure. The stent structure is made of corrugated shape memory alloy.

[0031] Specifically, the support structure in this embodiment is shown below. Figure 1 The fabrication of the scaffold structure was carried out according to the general methods in the existing technology.

[0032] S2: Preparation of drug-loaded nanomaterials S21: Using the sol-gel method, 5g of the template agent hexadecyltrimethylammonium bromide was dissolved in a mixture of 200mL deionized water and 2mL ammonia water. After thorough stirring, 20mL of tetraethyl orthosilicate was added, and the reaction was continued for 24h. After the reaction was completed, the precipitate was collected by centrifugation, the template agent was removed by washing, and the precipitate was dried to obtain mesoporous silica nanoparticles (MSNs). S22: 500 mg of mesoporous silica nanoparticles were dispersed in 50 mL of ethanol, and then 10 mL of 3-aminopropyltriethoxysilane (APTES) was added and stirred for 12 h to graft amino groups onto the surface of MSNs pores. After the reaction was completed, the nanoparticles were centrifuged, washed and dried to obtain amino-functionalized mesoporous silica nanoparticles (NH2-MSNs). S23: Dissolve 30 mg of antibacterial agent ciprofloxacin in 30 mL of ethanol, then add 100 mg of amino-functionalized mesoporous silica nanoparticles and stir for 24 h. Ciprofloxacin, due to its hydrophobicity, is adsorbed into the pores of MSNs through physical adsorption. After the reaction is complete, wash and dry to obtain mesoporous silica nanoparticles (NH2-MSNs@CIP) with antibacterial activity. S24: Dissolve 200 IU of the anticoagulant heparin in 20 mL of deionized water, then add 100 mg of mesoporous silica nanoparticles with antibacterial activity, stir and react for 24 h. Through electrostatic binding, heparin is further adsorbed on the surface of MSNs and the residual pore space. After the reaction is completed, wash and dry to obtain drug-loaded mesoporous silica nanoparticles.

[0033] S3: Assembly of the covered stent The preparation process of chitosan solution is as follows: dissolve chitosan in 3% acetic acid solution to form a 5% chitosan solution; Preparation of drug-loaded mesoporous silica nanoparticle dispersion: Disperse drug-loaded mesoporous silica nanoparticles in PBS buffer at a concentration of 10 mg / ml; Preparation process of hyaluronic acid solution: 1. Calculation: Weigh HA according to the target concentration.

[0034] 2. Preheating: Heat the solvent to 60°C.

[0035] 3. Dissolve: Slowly sprinkle in the weighed HA and stir continuously until transparent and free of particles (2~24 hours).

[0036] 4. Adjust pH: Use NaOH / HCl to adjust to 6-7.

[0037] 5. Sterilization: filtration (0.22μm) or autoclaving (121℃, 15min).

[0038] 6. Storage: Store at 4℃ away from light, add preservatives to obtain a hyaluronic acid solution with a concentration of 10 mg / mL.

[0039] After being activated by plasma cleaning at 200W for 20 minutes, the scaffold structure was first immersed in a chitosan solution to form a base layer for 0.5 hours. Then, it was alternately immersed in a drug-loaded mesoporous silica nanoparticle dispersion and a hyaluronic acid solution. The immersion time in the drug-loaded mesoporous silica nanoparticle dispersion was 1 hour, and the immersion time in the hyaluronic acid solution was 2 hours. This alternating immersion was repeated 5 times.

[0040] The specific process of forming a nano-coating on the surface of the scaffold structure using EDC / NHS chemical crosslinking is as follows: (1) After the last layer of hyaluronic acid solution is impregnated, the scaffold structure is removed and gently rinsed three times with 0.01mol / L pH=7.4 PBS solution to remove unbound hyaluronic acid; (2) Immediately afterwards, the scaffold structure was immersed in freshly prepared EDC / NHS crosslinking solution and reacted at 4°C under light-protected conditions for 24 hours. The crosslinking agent was prepared by dissolving EDC powder in MES buffer (pH 5.6) first, and then adding NHS powder after complete dissolution and gently mixing to obtain the crosslinking solution. The final crosslinking solution formula was: 50 mmol / L pH=5.5 MES buffer, 0.05 mol / L EDC·HCl, and 0.02 mol / L NHS. (3) After the reaction is completed, rinse three times each with 0.1 mol / L pH=7.4 Na2HPO4 and deionized water to terminate the reaction and remove residual crosslinking agent; (4) Finally, vacuum drying is used to form a nano-coating on the surface of the scaffold structure to obtain a membrane scaffold.

[0041] Test example 1. TEM tests were performed on the mesoporous silica nanoparticles (MSNs) prepared in step S21 of Example 1. The test results are shown in [the table below]. Figure 2 ,from Figure 2 As can be seen from the transmission electron microscope, the morphology and particle size of MSNs are approximately 250 nm in diameter, uniformly distributed, and the pores are clearly visible.

[0042] II. The antibacterial rate, biofilm analysis and animal model tests were performed on the mesoporous silica nanoparticles (NH2-MSNs@CIP) with antibacterial activity prepared in step S23 of Example 1.

[0043] (1) Antibacterial rate test: The experimental group achieved an antibacterial rate of 99.2% against Staphylococcus aureus (compared to only 12.1% in the control group). 1) Strains and Culture Strain: Staphylococcus aureus (S. aureus ATCC 25923) Culture medium: Mueller-Hinton (MH) broth Concentration: 1×10 6 CFU / mL (0.5 McFarland standard) 2) Experimental Procedure step experimental group control group Add materials <![CDATA[NH2-MSNs@CIP(100mg)]]> <![CDATA[NH2-MSNs(100mg)]]> Co-cultivation 37℃, 24h, oscillation (150rpm) Same experimental group sampling Spread 100 μL onto an MH agar plate Same experimental group count Count colonies after 24 hours at 37℃. Same experimental group 3) Result Calculation Antibacterial rate (%) = [(Control group CFU - Experimental group CFU) / Control group CFU] × 100.

[0044] Results: The antibacterial rate of the experimental group was 99.2%; the rate of the control group was 12.1% (only the carrier itself had weak antibacterial effect).

[0045] (2) Biofilm analysis: The biofilm thickness in the experimental group was reduced by 82% compared with that in the control group, and the proportion of live bacteria was less than 5%.

[0046] 1) Biofilm culture Method: 96-well plate method (crystal violet staining) Strain: S. aureus (same as above) Incubation time: 37℃, 48h (stationary incubation) 2) Experimental grouping and treatment Group Handling method detection indicators experimental group <![CDATA[NH2-MSNs@CIP (100 μg / mL) + bacterial solution]]> Biofilm thickness, viable bacteria ratio control group <![CDATA[NH2-MSNs (100 μg / mL) + bacterial solution]]> Same experimental group 3) Detection methods Thickness: Confocal laser scanning microscopy (CLSM, Syto9 / PI staining).

[0047] Viable bacteria ratio: ImageJ analysis of the ratio of red (dead) to green (live) fluorescence.

[0048] 4) Results: The biofilm thickness in the experimental group decreased by 82%.

[0049] The percentage of live bacteria is <5% (compared to approximately 60% in the control group).

[0050] (3) Animal experiments: 1) Animal model: Male SD rats (200~250g) Infection model: Subcutaneous implantation of a medical silicone scaffold (1 cm² surface area), followed by inoculation with S. aureus (10... 7 (CFU / mL, 100μL) 2) Experimental Grouping Group support coating quantity Observation time experimental group <![CDATA[NH2-MSNs@CIP(1mg / cm²)]]> n=6 7 days control group <![CDATA[NH2-MSNs (without drug)]]> n=6 7 days 3) Detection method: Colony counting: Remove on day 7, rinse with PBS, sonicate (5 min), serially dilute and spread on agar.

[0051] 4) Results: Experimental group: 10 3 CFU / cm 2 Control group: 10 7 CFU / cm 2 Log 10 The reduction value is 4 (i.e., 99.99% antibacterial effect).

[0052] III. The pore structure and specific surface area of ​​the drug-loaded mesoporous silica nanoparticles prepared in step S24 of Example 1 were analyzed by nitrogen adsorption-desorption (BET). The test results showed that the BET specific surface area of ​​the drug-loaded MSNs decreased compared to that of pure MSNs, from 950 μm. 2 / g decreased to 620m 2 / g, confirming successful drug loading.

[0053] IV. FTIR testing was performed on the nano-coating on the surface of the covered stent. The surface chemical modification and drug loading of the covered stent were verified using Fourier transform infrared spectroscopy (FTIR). Figure 3 As can be seen from this, the surface of the covered scaffold is at 1650 cm⁻¹ -1 The presence of amide bond characteristic peaks indicates successful cross-linking.

[0054] V. The coating of the coated scaffold prepared in Example 1 was subjected to performance testing. The specific testing process is as follows: (1) In vitro antibacterial test according to ISO 22196:2011 international standard: The covered scaffold fragment was subjected to an in vitro antibacterial test at a concentration of 10 6 The inhibition rate was calculated by incubating Staphylococcus aureus at CFU / mL for 24 hours and then counting the viable cells.

[0055] (2) Using SYTO 9 (labeled live bacteria) and propidium iodide (PI, labeled dead bacteria) double staining techniques, combined with three-dimensional imaging using laser confocal microscopy, the biofilm thickness and bacterial survival rate were quantitatively analyzed to evaluate the inhibitory effect of the coating on biofilm formation. Test results are shown below. Figure 4 .

[0056] (3) In the animal experimental model, 24 white rabbits weighing 2.5-3 kg were randomly divided into an experimental group (implanted with the covered stent prepared in Example 1) and a control group (implanted with a conventional stent) and underwent general anesthesia. The stent was implanted into the aortic segment of the rabbit's thoracic and abdominal thorax. After the blood vessels were anastomosed, 10 mg of ... 8 A CFU / mL suspension of Staphylococcus aureus was used to simulate a clinical postoperative infection scenario.

[0057] The stent was removed on the 7th day after surgery. The size of the antimicrobial zone was measured using the agar diffusion method. The test results are shown below. Figure 5 ,from Figure 5 It can be seen that the antibacterial zone around the stent is obvious and large, and no bacterial colonies grow within the zone.

[0058] Serum samples were collected on the third postoperative day, and the concentrations of inflammatory factors IL-6 and TNF-α were detected by ELISA. The test results are shown below. Figure 6 ,from Figure 6 The results showed that, compared with the preoperative level, the expression levels of IL-6 and TNF-α were significantly increased on the third postoperative day. However, the increase in these inflammatory factors after the use of the stent was significantly lower than that in the control group, indicating that the covered stent has a significant anti-inflammatory effect.

[0059] Animals were euthanized 4 weeks post-surgery, and the stent and surrounding tissues were harvested for HE staining. Intima coverage, thrombosis, and tissue inflammation were observed under a microscope. The test results are shown below. Figure 7 ,from Figure 7 As can be seen from the image, the tissue surrounding the stent shows less inflammatory cell infiltration, good intimal coverage, and no obvious thrombus formation. These observations indicate that the stent has excellent anti-inflammatory and tissue repair-promoting properties.

[0060] The results above show that the membrane-coated scaffold prepared by this invention has good biocompatibility and long-term safety.

[0061] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A method for preparing a thoracoabdominal aortic endovascular stent graft, characterized in that: The following steps are involved: S1: Design the support structure; S2: Preparation of drug-loaded nanomaterials S21: Using the sol-gel method, the template agent is dissolved in a mixture of deionized water and ammonia water. After thorough stirring, tetraethyl orthosilicate is added and the reaction is continued. After the reaction is completed, the precipitate is collected by centrifugation, the template agent is removed by washing, and the precipitate is dried to obtain mesoporous silica nanoparticles. S22: Mesoporous silica nanoparticles were dispersed in ethanol, and then 3-aminopropyltriethoxysilane was added and stirred. After the reaction was completed, the nanoparticles were centrifuged, washed and dried to obtain amino-functionalized mesoporous silica nanoparticles. S23: Dissolve the antibacterial agent in ethanol, then add amino-functionalized mesoporous silica nanoparticles, stir the reaction, and after the reaction is complete, wash and dry to obtain mesoporous silica nanoparticles with antibacterial effect. S24: Dissolve the anticoagulant in deionized water, then add mesoporous silica nanoparticles with antibacterial properties, stir the reaction, and after the reaction is complete, wash and dry to obtain drug-loaded mesoporous silica nanoparticles. S3: Assembly of the covered stent After plasma cleaning and activation, the scaffold structure is first immersed in a chitosan solution to form a base layer, and then alternately immersed in a drug-loaded mesoporous silica nanoparticle dispersion and a hyaluronic acid solution. After immersion, an EDC / NHS chemical crosslinking is used to form a nano-coating on the surface of the scaffold structure, and finally a membrane scaffold is obtained.

2. The method for preparing a thoracoabdominal aortic endovascular stent graft according to claim 1, characterized in that: In step S1, the stent structure includes a main stent and a movable stent. The main stent is divided into a dual-lumen shunt structure by a vertical partition. The large chamber is connected to the aorta, and a multi-modular shunt structure is embedded in the small chamber. The irregularly shaped connecting end of the movable stent is spliced ​​into multiple parts and forms a sealed interface with the multi-modular shunt structure. The stent structure is made of corrugated shape memory alloy.

3. The method for preparing a thoracoabdominal aortic endovascular stent graft according to claim 1, characterized in that: In step S21, the template agent is hexadecyltrimethylammonium bromide, and the addition ratio of hexadecyltrimethylammonium bromide, deionized water, ammonia and tetraethyl orthosilicate is 3~8g:150~250mL:1~3mL:15~25mL.

4. The method for preparing a thoracoabdominal aortic endovascular stent graft according to claim 1, characterized in that: In step S22, the mass-to-volume ratio of mesoporous silica nanoparticles to 3-aminopropyltriethoxysilane is 450~550 mg: 10 mL.

5. The method for preparing a thoracoabdominal aortic endovascular stent graft according to claim 1, characterized in that: In step S23, the antibacterial agent is ciprofloxacin, and the mass ratio of ciprofloxacin to amino-functionalized mesoporous silica nanoparticles is 25~35:

100.

6. The method for preparing a thoracoabdominal aortic endovascular stent graft according to claim 1, characterized in that: In step S24, the anticoagulant is heparin, and the addition ratio of heparin and mesoporous silica nanoparticles with antibacterial activity is 150~250 IU: 100 mg.

7. The method for preparing a thoracoabdominal aortic endovascular stent graft according to claim 1, characterized in that: In step S3, the parameters for plasma cleaning are: power 150~250W and processing time 5~30 minutes; The preparation process of chitosan solution is as follows: dissolve chitosan in 3% acetic acid solution to form a chitosan solution with a concentration of 3~8%; Preparation of drug-loaded mesoporous silica nanoparticle dispersion: Disperse drug-loaded mesoporous silica nanoparticles in PBS buffer at a concentration of 10 mg / ml; Preparation process of hyaluronic acid solution: Hyaluronic acid is added to a heated solvent to dissolve until a transparent solution is formed. The pH value is adjusted to 6-7, filtered and sterilized to obtain a hyaluronic acid solution with a concentration of 10 mg / mL.

8. The method for preparing a thoracoabdominal aortic endovascular stent graft according to claim 1, characterized in that: In step S3, the scaffold structure is immersed in the chitosan solution for 0.3~0.8 hours; The scaffold structure was immersed in the drug-loaded mesoporous silica nanoparticle dispersion for 0.5–1.5 h. The scaffold structure was immersed in hyaluronic acid solution for 2.5 to 3.5 hours. The number of alternating soaking times should be more than 5.

9. The method for preparing a thoracoabdominal aortic endovascular stent graft according to claim 1, characterized in that: In step S3, the specific process of forming a nano-coating on the surface of the scaffold structure using EDC / NHS chemical crosslinking is as follows: (1) After the last layer of hyaluronic acid solution impregnation is completed, the scaffold structure is removed and gently rinsed 3 times with 0.01mol / L pH=7.4 PBS solution to remove unbound hyaluronic acid; (2) Immediately afterwards, the scaffold structure was immersed in freshly prepared EDC / NHS crosslinking solution and reacted at 4°C under light-protected conditions for 12-24 hours. The crosslinking solution formula was: 50 mmol / L pH=5.5 MES buffer, 0.05 mol / L EDC·HCl, and 0.02 mol / L NHS. (3) After the reaction is completed, rinse three times each with 0.1 mol / L pH=7.4 Na2HPO4 and deionized water to terminate the reaction and remove residual crosslinking agent; (4) Finally, the film-coated scaffold is dried to obtain the final product.

10. A thoracoabdominal aortic endovascular stent graft, characterized in that: The thoracic and abdominal aortic endovascular stent, prepared by any one of claims 1 to 9, comprises a stent structure and a nano-coating, wherein the nano-coating is disposed on the surface of the stent structure.

Images