Esophageal stent covering film based on bacterial cellulose and waterborne polyurethane as well as preparation method and application of esophageal stent covering film

Abstract

The invention discloses an esophageal stent covering film based on bacterial cellulose and waterborne polyurethane as well as a preparation method and application of the esophageal stent covering film, and belongs to the technical field of medical stent covering films. The preparation method of the stent covering film comprises the following specific steps: preparing a SiR / PDA composite film by a dipping-oscillation method, putting the SiR / PDA composite film into an acetobacter xylinum fermentation culture solution to realize in-situ synthesis of BC on the film, mixing 5-Fu and a WPU emulsion, pouring the mixture onto the film, and drying to prepare the 5-Fu-WPU / BC / PDA / SiR esophageal stent covering film. The preparation method provided by the invention is relatively low in cost, the stent covering film based on BC and WPU prepared by the method has good swelling property, stability, thermal stability and mechanical property, and the loaded 5-Fu has stable drug release property. The esophageal stent can be effectively applied to local administration treatment of digestive tract diseases such as esophageal cancer, and a new technical scheme is provided for functional modification of a clinical esophageal stent.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medical stent covering, and particularly relates to an esophageal stent covering based on bacterial cellulose and waterborne polyurethane as well as a preparation method and application thereof. BACKGROUND

[0002] Esophageal stenosis is a kind of esophageal lumen stenosis caused by esophageal lesions or abnormal external pressure, with dysphagia as a typical symptom. Esophageal stenosis is divided into congenital esophageal stenosis and acquired esophageal stenosis. Congenital esophageal stenosis is caused by abnormal development of the esophagus during the embryonic period (such as residual tracheoesophageal fistula, membranous web formation), and is mostly seen in children, which needs early surgical intervention. Acquired stenosis accounts for the vast majority of adult cases, and the main causes include malignant tumors, benign lesions and external pressure stenosis. In addition to dysphagia, patients may also be accompanied by dysphagia, reflux esophagitis, weight loss and aspiration pneumonia and other complications. For malignant stenosis, the goal of palliative treatment is to relieve symptoms and prolong survival. For benign stenosis, long-term support is needed to prevent restenosis while minimizing treatment-related complications. Esophageal stent is a common palliative treatment for esophageal stenosis caused by esophageal cancer, which is mainly divided into bare stents and covered stents. The current clinical use of covered stents is mostly made of silicone (SiR), which can prevent tissue hyperplasia from embedding the stent, but has the problem of insufficient biocompatibility: long-term implantation, the silicone surface is easy to adsorb plasma protein, activate the complement system, and trigger foreign body reaction; single function, only provides a physical barrier, cannot inhibit tumor progression or promote tissue repair; insufficient mechanical properties, insufficient flexibility of silicone, easy to cause ulceration when rubbing with the pipe wall during esophageal peristalsis; poor fatigue resistance, repeated swallowing movements may cause cracks in the covering, increasing the risk of body fluid leakage and other defects. In addition to silicone covering, other covering materials also have their own problems, polytetrafluoroethylene (PTFE) has high chemical stability, but the biological inertness delays endothelialization, and long-term implantation is easy to form thrombosis or infection; degradable polymers (such as polylactic acid PLA) have uncontrollable degradation rate, and the mechanical strength decreases with time, which is difficult to meet the long-term support demand; metal bare stent materials such as nickel-titanium alloy have high strength but poor flexibility, and the release of metal ions may cause local toxicity reactions.

[0003] In summary, the existing esophageal stent covering materials have different degrees of defects in biocompatibility, functional diversity and mechanical properties. Insufficient biocompatibility may trigger immune and inflammatory reactions in the human body, affecting the rehabilitation and quality of life of patients; single function cannot meet the more complex treatment needs of tumor inhibition and tissue repair; poor mechanical properties will cause the covering to be damaged, leaked and other problems during use, shorten the service life of the stent, and increase the pain and treatment cost of patients. Therefore, it is of great practical significance to develop a new type of esophageal stent covering material. SUMMARY

[0004] In view of the problems of insufficient biocompatibility, single function and poor mechanical performance of existing esophageal stent covering materials, the purpose of the present application is to provide an esophageal stent covering based on bacterial cellulose (BC) and water-based polyurethane (WPU) as well as a preparation method and application thereof.

[0005] In order to achieve the above-mentioned purpose, the present application adopts the following technical solutions to achieve it: The present application provides an esophageal stent covering based on bacterial cellulose and water-based polyurethane, which is composed of a silica gel film support layer, a polydopamine adhesion layer (PDA adhesion layer), a bacterial cellulose layer and a water-based polyurethane layer from bottom to top, and an anticancer drug 5-fluorouracil loaded in the bacterial cellulose layer and the water-based polyurethane layer.

[0006] The silica gel film support layer and the polydopamine adhesion layer are combined by covalent bond.

[0007] The polydopamine adhesion layer and the bacterial cellulose layer are combined by in-situ synthesis.

[0008] The bacterial cellulose layer and the water-based polyurethane layer are combined by hydrogen bond action.

[0009] The anticancer drug 5-fluorouracil loaded in the bacterial cellulose layer and the water-based polyurethane layer is embedded in the molecular network structure of the bacterial cellulose layer and the water-based polyurethane by the mechanical wrapping effect of Van der Waals force and three-dimensional network structure.

[0010] The present application provides a preparation method of the above-mentioned esophageal stent covering based on bacterial cellulose and water-based polyurethane, which comprises: Step 1, immerse the silica gel film in the dopamine solution, shake culture, sterilization, and obtain the composite film loaded with polydopamine; Step 2, place the composite film loaded with polydopamine into the bacterial cellulose fermentation medium, in-situ synthesis, and obtain composite film 1; Step 3, mix the emulsion and coat it on the composite film 1, and dry to obtain the esophageal stent covering based on bacterial cellulose and water-based polyurethane; The mixed emulsion is obtained by mixing 5-fluorouracil solution and water-based polyurethane emulsion (solid content 40%).

[0011] In step 1, the shaking culture temperature is 34 ℃~36 ℃, the rotation speed is 100 r / min~200 r / min, and the culture time is 24 h~72 h.

[0012] In step 2, the in-situ synthesis is room temperature culture for 10 d~15 d.

[0013] In step 3, the mass ratio of 5-fluorouracil solution to water-based polyurethane emulsion is (3~5):3.

[0014] In step 3, the drying temperature is 35-55 DEG C, and the drying time is 48-72 h.

[0015] The application provides application of the esophageal stent coating film based on bacterial cellulose and water-based polyurethane in preparation of an esophageal disease medicine.

[0016] Compared with the prior art, the application has the following beneficial effects: The esophageal stent coating film based on bacterial cellulose and water-based polyurethane provided by the application has the following advantages: the silica gel film support layer provides mechanical support as a substrate, and the flexibility thereof can adapt to esophageal peristalsis, thereby reducing the risk of friction damage; the polydopamine adhesion layer is combined with the silica gel film through a covalent bond, so that the interfacial bonding strength is enhanced, and interlayer peeling is avoided; the bacterial cellulose layer is combined with the polydopamine layer through in-situ synthesis, the natural three-dimensional network structure of the bacterial cellulose layer is used to load drugs, the high water retention improves biocompatibility, and the foreign body reaction is reduced; the water-based polyurethane layer is combined with the bacterial cellulose through hydrogen bonds, so that a flexible molecular network structure is formed; the loaded five-fluorouracil is embedded in the bacterial cellulose and the water-based polyurethane molecular network through van der Waals force, so that the slow-release function of the anticancer drug is realized, and the anticancer drug directly acts on a tumor site.

[0017] Further, the polydopamine adhesion layer reacts with hydroxyl groups on the surface of the silica gel film through the rich catechol groups on the surface of the polydopamine adhesion layer, so that a stable covalent connection network is formed, the chemical bonding mode can significantly reduce the risk of interlayer peeling, and the structural integrity of the coating film in the dynamic environment of the esophagus is ensured. Meanwhile, the covalent bond combination avoids the biocompatibility problems that may be caused by the use of additional adhesives, so that the functional layers of the coating film form an organic whole, and a stable substrate is provided for the in-situ synthesis of the bacterial cellulose layer. The active surface of the polydopamine is used as a substrate for the biosynthesis of bacterial cellulose. The polydopamine adhesion layer is rich in functional groups such as amino groups and phenolic hydroxyl groups, and can provide anchoring sites for the microbial fermentation process of bacterial cellulose, so as to promote the bacteria to directly secrete nanocellulose fibers on the surface of the adhesion layer. This in-situ growth mode enables the bacterial cellulose layer and the polydopamine adhesion layer to form a molecular-level interpenetrating network structure, which significantly enhances the interfacial bonding strength compared with traditional composite methods such as physical coating or chemical crosslinking. At the same time, the biocompatibility risk caused by the introduction of exogenous adhesives is avoided, so that the coating film can still maintain structural integrity when resisting mechanical stress in the dynamic environment of the esophagus, thereby overcoming the defects of poor fatigue resistance and easy cracking and leakage of the silica gel coating film due to weak interfacial bonding.

[0018] The application provides a preparation method of an esophageal stent coating film based on bacterial cellulose and water-based polyurethane, wherein a multi-layer composite structure is constructed in steps to realize function integration and structure optimization of the coating film material. A dopamine hydrochloride solution is used to impregnate a silica gel film, a stable covalent bond interface is formed by using the adhesion property of polydopamine to provide a reliable support substrate for subsequent layers, bacterial cellulose is made to grow on the surface of the composite film loaded with polydopamine in an in-situ synthesis manner to form a biocompatible layer with a three-dimensional network structure, and an anticancer drug is mixed with a water-based polyurethane emulsion to be coated to realize physical embedding and slow-release control of the drug by using the molecular network structure of the water-based polyurethane.

[0019] Further, the shaking table culture parameters control the polymerization degree of polydopamine, the in-situ synthesis time guarantees sufficient growth of the bacterial cellulose, the mixed emulsion ratio optimizes the drug loading efficiency, and the drying conditions ensure the tightness of the interlayer combination; the coating film prepared by the method has mechanical support, drug slow-release and biodegradation properties, and the functional layers form a stable composite system through different forces.

[0020] The application provided by the application realizes multifunctional integration of esophageal disease treatment by applying the coating film material with a specific layered structure to drug preparation, wherein the silica gel film support layer is combined with the polydopamine adhesion layer through a covalent bond, which guarantees the structural stability of the material and enhances the interfacial bonding strength; the in-situ synthesized bacterial cellulose layer is combined with the water-based polyurethane layer through hydrogen bonding to form a composite carrier with excellent biocompatibility; the bacterial cellulose and the water-based polyurethane molecular network are embedded with the anticancer drug five-fluorouracil through van der Waals force to construct a slow-release drug delivery system. The interlayer synergistic effect enables the coating film to maintain the patency of the esophageal lumen after implantation, continuously release the anticancer drug to inhibit tumor cell proliferation, reduce foreign body reactions through the biocompatibility design of the layers of materials, and finally realize the dual functions of esophageal stricture treatment and tumor inhibition. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 is a tensile test diagram of embodiments 1-3 of the application; Figure 2 is a stability experiment diagram of the esophageal stent coating film of embodiments 1-3 of the application; Figure 3 is a thermal stability curve diagram of the esophageal stent coating film of embodiments 1-3 of the application; Figure 4 is a swelling curve diagram of the esophageal stent coating film of embodiments 1-3 of the application; Figure 5 is a drug release curve diagram of the esophageal stent coating film of embodiments 4-6 of the application; Figure 6 is a SEM diagram of the esophageal stent coating film of embodiment 4 of the application, wherein A is the front view and B is the cross section. Figure 7 is the SEM diagram of the esophageal stent covering film of the embodiment 5 of the present application, wherein A is the front view and B is the cross section; Figure 8 is the SEM diagram of the esophageal stent covering film of the embodiment 6 of the present application, wherein A is the front view and B is the cross section. DETAILED DESCRIPTION

[0022] In order to make the personnel in the art better understand the present application, the technical solutions in the embodiments of the present application will be described clearly and completely below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor should belong to the scope of protection of the present application.

[0023] It should be noted that the terms "first", "second" and the like used in the specification and claims are only used to distinguish similar objects, and do not necessarily describe a specific order or sequence; it should be understood that these terms can be interchanged with each other under appropriate circumstances. In addition, the terms "include", "have" and any variations thereof are intended to cover non-exclusive inclusion; for example, a process, method, system, product or device that includes a series of steps or units does not necessarily limit to the steps or units explicitly listed, but can include other steps or units not explicitly listed or inherent thereto.

[0024] The drawings will be described below in conjunction with the Figures 1-8 The present application will be described in further detail; Embodiment 1 The present embodiment provides an esophageal stent covering film based on bacterial cellulose and water-based polyurethane, and the specific preparation steps are as follows: Step 1, preparation of PDA / SiR composite film After the silica gel film (SiR film) is washed with distilled water, it is dried and cut into a 5.5 cm diameter disc; the cut SiR film is fixed on a 6 cm diameter plastic ring with cotton thread to prevent it from sticking to the wall during shaking; the fixed SiR film is placed in a 2 mg / mL dopamine hydrochloride solution (hydrochloric acid PDA solution, solvent is Tris buffer solution) to ensure that the SiR film is completely immersed in the solution; it is placed in a shaker and shaken at 35 ℃ and 100 r / min for 24 h; after shaking, it is sterilized in a high-pressure sterilization pot at 121 ℃ for 20 min to obtain a PDA / SiR composite film; Step 2, preparation of BC / PDA / SiR composite film The wood vinegar bacillus Acetobacter xylinum(From the General Microbial Culture Collection Center of China) was inoculated into the fermentation medium (sucrose 60 g / L, beef extract 15 / L, sodium dihydrogen phosphate 4.4 g / L, citric acid 0.8 g / L, ethanol 10 ml / L) at a ratio of 10%, and a culture medium containing Bacillus acidophilus was obtained; the polyPDA / SiR composite film obtained in step 1 was placed in the culture medium containing Bacillus acidophilus, and the composite film was completely immersed in the culture medium, and cultured for 10 days to obtain a polyPDA / SiR composite film with a bacterial cellulose layer; after the culture was completed, the polyPDA / SiR composite film with the bacterial cellulose layer was placed in a 1% (w / w) sodium hydroxide solution at 90°C for 3 h, then soaked in pure water, and the water was changed every 24 h until both sides of the film were colorless, and then the film was stored in water, to obtain a BC / PDA / SiR composite film; Step 3, applying the mixed emulsion A 5-fluorouracil (5-Fu) solution with a concentration of 12 μg / mL was prepared using PBS; the 5-fluorouracil (5-Fu) solution was mixed with the aqueous polyurethane (WPU) emulsion (purchased from Shanghai Melin Biochemical Technology Co., Ltd., solid content 40%) at a volume ratio of 1:1 to obtain a mixed emulsion; the BC / PDA / SiR composite film prepared in step 2 was placed in a polytetrafluoroethylene dish (inner diameter 6 cm, height 2 cm), and the mixed emulsion was coated on the surface of the BC / PDA / SiR composite film using a coater, with the mass ratio of the mixed emulsion to the composite film being 3:3; the composite film coated with the mixed emulsion was placed in an oven together with the polytetrafluoroethylene dish, and dried at 35°C for 48 h; then the composite film was taken out of the oven and cooled to room temperature; the composite film was removed from the plastic ring to obtain a 5-Fu-WPU / BC / PDA / SiR drug-loaded esophageal stent coating film.

[0025] Example 2 The present embodiment provides an esophageal stent coating film based on bacterial cellulose and aqueous polyurethane, and the specific preparation steps are as follows: Step 1, preparation of polyPDA / SiR composite film The SiR film was washed with distilled water and then air-dried, and was cut into a 5.5 cm diameter disc; the cut SiR film was fixed on a plastic ring with an outer diameter of 6 cm using cotton thread to prevent it from sticking to the wall during shaking, and a fixed SiR film was obtained; the fixed SiR film was placed in a dopamine hydrochloride solution with a concentration of 2 mg / mL (solvent: Tris buffer) to ensure that the SiR film was completely immersed in the solution; it was placed in a shaking bed and treated at 35°C and 150 r / min for 36 h; after shaking, high-pressure sterilization was performed using a high-pressure sterilization pot at 121°C for 20 min to obtain a polyPDA / SiR composite film; Step 2, preparation of BC / PDA / SiR composite film Acetobacter xylinum Acetobacter xylinum Acetobacter xylinum (purchased from China General Microbiological Culture Collection Center) was inoculated into fermentation medium (sucrose 60 g / L, beef extract 15 / L, sodium dihydrogen phosphate 4.4 g / L, citric acid 0.8 g / L, ethanol 10 ml / L) at a ratio of 10%, to obtain a culture medium containing Acetobacter xylinum; the polyPDA / SiR composite film obtained in step 1 was placed in the culture medium containing Acetobacter xylinum, ensuring that the composite film was completely immersed in the culture medium, and cultured for 12 d to obtain a polyPDA / SiR composite film with a bacterial cellulose layer; after the culture was completed, the polyPDA / SiR composite film with the bacterial cellulose layer was placed in a 1% (w / w) sodium hydroxide solution at 90 ℃ for 3 h, then soaked in pure water, and the water was changed every 24 h until both sides of the film were colorless, and then the film was stored in water, to obtain a BC / PDA / SiR composite film; Step 3, applying the mixed emulsion A 5-fluorouracil (5-Fu) solution with a concentration of 12 μg / mL was prepared using PBS; the 5-fluorouracil (5-Fu) solution was mixed with a waterborne polyurethane (WPU) emulsion (solid content 40%) at a volume ratio of 1:1 to obtain a mixed emulsion; the BC / PDA / SiR composite film prepared in step 2 was placed in a polytetrafluoroethylene dish (inner diameter 6 cm, height 2 cm), and the mixed emulsion was applied to the surface of the BC / PDA / SiR composite film using a coater, with the mass ratio of the mixed emulsion to the composite film being 4:3; the composite film with the applied mixed emulsion was placed in an oven together with the polytetrafluoroethylene dish, and dried at 45 ℃ for 60 h; after drying, the composite film was removed from the oven and cooled to room temperature; the composite film was then removed from the plastic ring, to obtain a 5-Fu-WPU / BC / PDA / SiR drug-loaded esophageal stent coating film.

[0026] Example 3 The present example provides an esophageal stent coating film based on bacterial cellulose and waterborne polyurethane, and the specific preparation steps are as follows: Step 1, preparation of a polyPDA / SiR composite film The SiR film was washed with distilled water and then air-dried, and cut into a 5.5 cm diameter disc; the cut SiR film was fixed to a plastic ring with an outer diameter of 6 cm using cotton thread to prevent it from sticking to the wall during shaking, to obtain a fixed SiR film; the fixed SiR film was placed in a dopamine hydrochloride solution with a concentration of 2 mg / mL (solvent: Tris buffer), ensuring that the SiR film was completely immersed in the solution; the film was placed in a shaking bed and treated at 35 ℃ with 200 r / min shaking for 48 h; after shaking, the polyPDA / SiR composite film was obtained by high-temperature sterilization in an autoclave at 121 ℃ for 20 min; Step 2, preparation of a BC / PDA / SiR composite film Acetobacter xylinum Acetobacter xylinum Acetobacter xylinum (purchased from China General Microbiological Culture Collection Center) was inoculated into fermentation medium (sucrose 60 g / L, beef extract 15 / L, sodium dihydrogen phosphate 4.4 g / L, citric acid 0.8 g / L, ethanol 10 ml / L) at a ratio of 10%, to obtain a culture medium containing Acetobacter xylinum; the polyPDA / SiR composite film obtained in step 1 was placed in the culture medium containing Acetobacter xylinum, ensuring that the composite film was completely immersed in the culture medium, and cultured for 15 d to obtain a polyPDA / SiR composite film with a bacterial cellulose layer; after the culture was completed, the polyPDA / SiR composite film with the bacterial cellulose layer was placed in a 1% (w / w) sodium hydroxide solution at 90 ℃ for 3 h, then soaked in pure water, and the water was changed every 24 h until both sides of the film were colorless, and then the film was stored in water, to obtain a BC / PDA / SiR composite film; Step 3, applying the mixed emulsion A 5-fluorouracil (5-Fu) solution with a concentration of 12 μg / mL was prepared using PBS; the 5-fluorouracil (5-Fu) solution was mixed with a waterborne polyurethane (WPU) emulsion (solid content 40%) at a volume ratio of 1:1 to obtain a mixed emulsion; the BC / PDA / SiR composite film prepared in step 2 was placed in a polytetrafluoroethylene dish (inner diameter 6 cm, height 2 cm), and the mixed emulsion was applied to the surface of the BC / PDA / SiR composite film using a coater, with the mass ratio of the mixed emulsion to the composite film being 5:3; the composite film with the applied mixed emulsion was placed in an oven together with the polytetrafluoroethylene dish, and dried at 50 ℃ for 72 h; then the composite film was removed from the oven and cooled to room temperature; the composite film was removed from the plastic ring, and a 5-Fu-WPU / BC / PDA / SiR drug-loaded esophageal stent coating film was obtained.

[0027] Example 4 The present example provides an esophageal stent coating film based on bacterial cellulose and waterborne polyurethane, and the specific preparation steps are as follows: Step 1, preparation of polyPDA / SiR composite film The SiR film was washed with distilled water and then air-dried, and cut into a 5.5 cm diameter disc; the cut SiR film was fixed to a plastic ring with an outer diameter of 6 cm using cotton thread to prevent it from sticking to the wall during shaking, to obtain a fixed SiR film; the fixed SiR film was placed in a dopamine hydrochloride solution with a concentration of 2 mg / mL (solvent: Tris buffer), ensuring that the SiR film was completely immersed in the solution; the shaking was performed in a shaking bed at 35 ℃ and 100 r / min for 24 h; after the shaking was completed, high-pressure sterilization was performed using an autoclave at 121 ℃ for 20 min, to obtain a polyPDA / SiR composite film; Step 2, preparation of BC / PDA / SiR composite film Acetobacter xylinum Acetobacter xylinum Acetobacter xylinum (purchased from China General Microbiological Culture Collection Center) was inoculated into fermentation medium (sucrose 60 g / L, beef extract 15 / L, sodium dihydrogen phosphate 4.4 g / L, citric acid 0.8 g / L, ethanol 10 mL / L) at a ratio of 10%, to obtain a culture medium containing Acetobacter xylinum; the polyPDA / SiR composite film obtained in step 1 was placed in the culture medium containing Acetobacter xylinum, ensuring that the composite film was completely immersed in the culture medium, and cultured for 12 d to obtain a polyPDA / SiR composite film with a bacterial cellulose layer; after the culture was completed, the polyPDA / SiR composite film with the bacterial cellulose layer was placed in a 1% (w / w) sodium hydroxide solution at 90 ℃ for 3 h, then soaked in pure water, and the water was changed every 24 h until both sides of the film were colorless, and then the film was stored in water, to obtain a BC / PDA / SiR composite film; Step 3, applying the mixed emulsion A 5-fluorouracil (5-Fu) solution with a concentration of 12 μg / mL was prepared using PBS; the 5-fluorouracil (5-Fu) solution was mixed with the waterborne polyurethane (WPU) emulsion (solid content 40%) at a volume ratio of 1:1 to obtain a mixed emulsion; the BC / PDA / SiR composite film prepared in step 2 was placed in a polytetrafluoroethylene dish (inner diameter 6 cm, height 2 cm), and the mixed emulsion was applied to the surface of the BC / PDA / SiR composite film using a coater, with the mass ratio of the mixed emulsion to the composite film being 3:3; the composite film with the applied mixed emulsion was placed in an oven together with the polytetrafluoroethylene dish, and dried at 35 ℃ for 48 h; then the composite film was taken out of the oven and cooled to room temperature, and removed from the plastic ring to obtain a 5-Fu-WPU / BC / PDA / SiR drug-loaded esophageal stent coating film.

[0028] Example 5 The present example provides an esophageal stent coating film based on bacterial cellulose and waterborne polyurethane, and the specific preparation steps are as follows: Step 1, preparation of polyPDA / SiR composite film The SiR film was washed with distilled water and then air-dried, and cut into a 5.5 cm diameter disc; the cut SiR film was fixed to a plastic ring with an outer diameter of 6 cm using cotton thread to prevent it from sticking to the wall during shaking, to obtain a fixed SiR film; the fixed SiR film was placed in a dopamine hydrochloride solution with a concentration of 2 mg / mL (solvent: Tris buffer) to ensure that the SiR film was completely immersed in the solution; it was placed in a shaking bed and treated at 35 ℃ with 100 r / min shaking for 24 h; after shaking, high-pressure sterilization was performed using an autoclave at 121 ℃ for 20 min to obtain a polyPDA / SiR composite film; Step 2, preparation of BC / PDA / SiR composite film Acetobacter xylinum Acetobacter xylinum Acetobacter xylinum (purchased from China General Microbiological Culture Collection Center) was inoculated into fermentation medium (sucrose 60 g / L, beef extract 15 / L, sodium dihydrogen phosphate 4.4 g / L, citric acid 0.8 g / L, ethanol 10 ml / L) at a ratio of 10%, to obtain a culture medium containing Acetobacter xylinum; the polyPDA / SiR composite film obtained in step 1 was placed in the culture medium containing Acetobacter xylinum, ensuring that the composite film was completely immersed in the culture medium, and cultured for 12 d to obtain a polyPDA / SiR composite film with a bacterial cellulose layer; after the culture was completed, the polyPDA / SiR composite film with the bacterial cellulose layer was placed in a 1% (w / w) sodium hydroxide solution at 90 ℃ for 3 h, then soaked in pure water, and the water was changed every 24 h until both sides of the film were colorless, and then the film was stored in water, to obtain a BC / PDA / SiR composite film; Step 3, applying the mixed emulsion A 5-fluorouracil (5-Fu) solution with a concentration of 12 μg / mL was prepared using PBS; the 5-fluorouracil (5-Fu) solution was mixed with a waterborne polyurethane (WPU) emulsion (solid content 40%) at a volume ratio of 1:1 to obtain a mixed emulsion; the BC / PDA / SiR composite film prepared in step 2 was placed in a polytetrafluoroethylene dish (inner diameter 6 cm, height 2 cm), and the mixed emulsion was applied to the surface of the BC / PDA / SiR composite film using a coater, with the mass ratio of the mixed emulsion to the composite film being 3:3; the composite film with the applied mixed emulsion was placed in an oven together with the polytetrafluoroethylene dish, and dried at 35 ℃ for 48 h; then the composite film was taken out of the oven and cooled to room temperature, and removed from the plastic ring to obtain a 5-Fu-WPU / BC / PDA / SiR drug-loaded esophageal stent coating film.

[0029] Example 6 The present example provides an esophageal stent coating film based on bacterial cellulose and waterborne polyurethane, and the specific preparation steps are as follows: Step 1, preparation of polyPDA / SiR composite film The SiR film was washed with distilled water and then air-dried, and cut into a 5.5 cm diameter disc; the cut SiR film was fixed to a plastic ring with an outer diameter of 6 cm using cotton thread to prevent it from sticking to the wall during shaking, to obtain a fixed SiR film; the fixed SiR film was placed in a dopamine hydrochloride solution with a concentration of 2 mg / mL (solvent: Tris buffer) to ensure that the SiR film was completely immersed in the solution; it was placed in a shaking bed and treated at 35 ℃ with 100 r / min shaking for 24 h; after shaking, high-pressure sterilization was performed using an autoclave at 121 ℃ for 20 min to obtain a polyPDA / SiR composite film; Step 2, preparation of BC / PDA / SiR composite film Acetobacter xylinum Acetobacter xylinum Step 1, preparation of BC / PDA / SiR composite membrane Acetobacter xylinum (purchased from China General Microbiological Culture Collection Center) was inoculated into fermentation medium (sucrose 60 g / L, beef extract 15 / L, sodium dihydrogen phosphate 4.4 g / L, citric acid 0.8 g / L, ethanol 10 mL / L) at a ratio of 10%, to obtain a culture medium containing Acetobacter xylinum; the polyPDA / SiR composite membrane obtained in step 1 was placed in the culture medium containing Acetobacter xylinum, ensuring that the composite membrane was completely immersed in the culture medium, and cultured for 12 d to obtain a polyPDA / SiR composite membrane with a bacterial cellulose layer; after the culture was completed, the polyPDA / SiR composite membrane with the bacterial cellulose layer was placed in a 1% (w / w) sodium hydroxide solution at 90 ℃ for 3 h, then soaked in pure water, and the water was changed every 24 h until the two sides of the membrane were colorless, and then the membrane was stored in water, to obtain a BC / PDA / SiR composite membrane; Step 3, application of mixed emulsion A 5-fluorouracil (5-Fu) solution with a concentration of 12 μg / mL was prepared using PBS; the 5-fluorouracil (5-Fu) solution was mixed with a waterborne polyurethane (WPU) emulsion (solid content 40%) at a volume ratio of 1:1 to obtain a mixed emulsion; the BC / PDA / SiR composite membrane prepared in step 2 was placed in a polytetrafluoroethylene dish (inner diameter 6 cm, height 2 cm), and the mixed emulsion was applied to the surface of the BC / PDA / SiR composite membrane using a coater, with the mass ratio of mixed emulsion to composite membrane being 3:3; the composite membrane with the applied mixed emulsion was placed in an oven together with the polytetrafluoroethylene dish, and dried at 35 ℃ for 48 h; then the composite membrane was removed from the oven and cooled to room temperature, and removed from the plastic ring to obtain a 5-Fu-WPU / BC / PDA / SiR drug-loaded esophageal stent coating film.

[0030] II. Performance test 1. Elongation at break and tensile strength An AI-7000-NGD servo-controlled high-low temperature tensile testing machine (Gotech, Tianjin) was used, and the composite membrane samples of Examples 1-3 were respectively installed on the clamps of the tensile testing machine for tensile testing; when the sample was broken, the test data of the sample was saved, and each experimental group was repeated 3 times; the test results are shown in Table 1. Figure 1 .

[0031] Table 1 Figure 1Data shows that the composite membranes of Examples 1-3 all exhibit high elongation at break and tensile strength, meeting the mechanical requirements for scaffold coating. As the mass ratio of the mixed emulsion to the BC / PDA / SiR composite membrane increases, the elongation at break of the composite membrane continuously increases, but the tensile strength shows a decreasing trend. This is because the components in the mixed emulsion increase the flexibility and molecular chain mobility of the composite membrane, making it easier to deform during stretching, thus improving the elongation at break. However, the increased proportion of the mixed emulsion leads to a decrease in the interfacial bonding strength between the mixed emulsion and the BC / PDA / SiR composite membrane, resulting in a decrease in tensile strength. Among these, the composite membrane of Example 1 exhibits an elongation at break exceeding 100% and better tensile strength, indicating that the composite membrane formulation and preparation process of Example 1 have advantages in comprehensive mechanical properties, better balancing flexibility and strength, and are more suitable as a scaffold coating material.

[0032] 2. Stability The coating materials prepared in Examples 1-3 were immersed in PBS buffer and subjected to a simulated body fluid environment at 37°C, pH 5.5, and a shaker speed of 100 r / min for 14 days. During this period, the state of the samples in the simulated body fluid was observed periodically, and any significant changes were recorded. The obtained data on leachable content were statistically analyzed. Specific results are detailed in the appendix. Figure 2 As shown.

[0033] From the appendix Figure 2 Data shows that the leachable content of the coating materials in Examples 1-3 was no more than 0.4% after 14 days in a simulated environment. This indicates that the coating materials have excellent stability in a simulated body fluid environment and hardly undergo degradation or release of harmful substances in long-term body fluid, thus meeting the safety requirements for medical implant materials.

[0034] 3. Thermal stability The thermal stability of the esophageal stent membranes in Examples 1-3 was tested using a STA409PC simultaneous thermal analyzer (NEZ Instruments, Germany). The test results are shown in the appendix. Figure 3 As shown. (From the appendix) Figure 3 The data shows that the esophageal stent coatings of Examples 1-3 had a weight loss rate of approximately 6% in the first stage (room temperature to 280 ℃), indicating that the material only experienced a small amount of mass loss within a relatively low temperature range, demonstrating good stability in the temperature range from room temperature to 280 ℃. In the second stage (280-450 ℃), the weight loss rate was approximately 80-85%, and the temperature corresponding to the maximum rate of thermal weight loss was 425 ℃, indicating that the esophageal stent coatings prepared in Examples 1-3 all have excellent thermal stability and can adapt to a wide range of applications, especially maintaining stable performance under different temperature environments.

[0035] As shown in Figure 4 , the swelling degrees of the esophageal stent cover films of Examples 1-3 all exceed 60 %, which have good swelling performance and are of great significance for the esophageal stent cover films. At room temperature, the good swelling performance enables the cover film to closely adhere to the esophageal mucosa, which helps to reduce the gap between the cover film and the esophageal mucosa, improve the stability of the stent in the esophagus, and also facilitates the effective release and local action of the drug; the close adhesion to the esophageal mucosa can enhance the interaction between the cover film and the esophageal tissue, thereby reducing the risk of displacement of the stent in the esophagus and ensuring that the stent can continuously and stably exert its supporting and therapeutic effects.

[0036] As shown in Figure 5 , the drug release of the esophageal stent cover films of Examples 4-6 in PBS buffer at room temperature for 60 h all exceeds 60 %, and the release process of 5-Fu presents the characteristics of fast first and slow later, with a faster release rate in the initial 24 h to rapidly reach an effective therapeutic concentration; then a steady release trend is maintained for 36 h, and such release kinetics characteristics are conducive to realizing the long-acting sustained release of the drug and meeting the clinical needs of treatment.

[0037] The apparent structure of Examples 4-6 was tested by high-resolution field scanning transmission electron microscopy, and the results Figures 6-8 were obtained. As shown in Figures 5-7 , with the increase of the drug content of the composite film, the number of drug particles observed on the film surface and cross-section increases.

[0038] The above content only illustrates the technical idea of the present application and cannot limit the protection scope of the present application. Any modification made according to the technical idea of the present application on the basis of the technical solution falls within the protection scope of the claims of the present application.

Claims

1. An esophageal stent coating based on bacterial cellulose and aqueous polyurethane, characterized in that, The esophageal stent membrane consists of, from bottom to top, a silicone membrane support layer, a polydopamine adhesion layer, a bacterial cellulose layer, and an aqueous polyurethane layer, as well as the anticancer drug 5-fluorouracil loaded in the bacterial cellulose layer and the aqueous polyurethane layer.

2. The esophageal stent membrane based on bacterial cellulose and aqueous polyurethane according to claim 1, characterized in that, The silicone film support layer and the polydopamine adhesion layer are bonded together by covalent bonds.

3. The esophageal stent membrane based on bacterial cellulose and aqueous polyurethane according to claim 1, characterized in that, The polydopamine adhesion layer and the bacterial cellulose layer are combined through in-situ synthesis.

4. The esophageal stent membrane based on bacterial cellulose and aqueous polyurethane according to claim 1, characterized in that, The bacterial cellulose layer and the aqueous polyurethane layer are bonded together by hydrogen bonding; the anticancer drug 5-fluorouracil loaded in the bacterial cellulose layer and the aqueous polyurethane layer is embedded in the molecular network structure of the bacterial cellulose layer and the aqueous polyurethane layer through van der Waals forces and the mechanical encapsulation effect of the three-dimensional network structure.

5. A method for preparing an esophageal stent membrane based on bacterial cellulose and aqueous polyurethane as described in any one of claims 1 to 4, characterized in that, include: Step 1: Immerse the silica membrane in dopamine solution, incubate on a shaker, sterilize, and obtain a composite membrane loaded with polydopamine; Step 2: The composite membrane loaded with polydopamine is placed in a bacterial cellulose fermentation medium for in-situ synthesis to obtain composite membrane 1. Step 3: The mixed emulsion is coated onto composite membrane 1 and dried to obtain an esophageal stent membrane based on bacterial cellulose and waterborne polyurethane. The mixed emulsion is prepared by mixing a 5-fluorouracil solution and an aqueous polyurethane emulsion.

6. The method for preparing an esophageal stent membrane based on bacterial cellulose and aqueous polyurethane according to claim 5, characterized in that, In step 1, the shaking incubation temperature is 34 ℃~36 ℃, the rotation speed is 100 r / min~200 r / min, and the incubation time is 24 h~72 h.

7. The method for preparing an esophageal stent membrane based on bacterial cellulose and aqueous polyurethane according to claim 5, characterized in that, In step 2, the in-situ synthesis involves incubation at room temperature for 10-15 days.

8. The method for preparing an esophageal stent membrane based on bacterial cellulose and aqueous polyurethane according to claim 5, characterized in that, In step 3, the mass ratio of the 5-fluorouracil solution to the aqueous polyurethane emulsion is (3~5):

3.

9. The method for preparing an esophageal stent membrane based on bacterial cellulose and aqueous polyurethane according to claim 5, characterized in that, In step 3, the drying temperature is 35 ℃~55 ℃, and the drying time is 48 h~72 h.

10. The use of the esophageal stent membrane based on bacterial cellulose and aqueous polyurethane as described in any one of claims 1 to 4 in the preparation of esophageal disease drugs.

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