4D printing esophageal stent and preparation method thereof

Abstract

This invention provides a 4D-printed esophageal stent and its preparation method. The esophageal stent includes a stent body and a drug-loaded fiber membrane with a core-shell structure. The stent body is a tubular stent composed of a biomimetic water lily-like perforated structure. The diameters of the first and last ends of the stent body are larger than the diameter of the middle section, and the outer surfaces of the first and last ends are provided with barbed structures. The stent body is made of a biodegradable shape memory polymer. The drug-loaded fiber membrane is located on the outer surface of the middle section of the stent body and contains drugs. The 4D-printed esophageal stent provided by this invention has excellent compressive strength and anti-slip ability, and the drug-loaded fiber membrane can prevent esophageal restenosis through long-term uniform and sustained drug release, further ensuring patient safety.

Description

Technical Field

[0001] This invention relates to the field of medical material manufacturing technology, and in particular to a 4D-printed esophageal stent and its preparation method. Background Technology

[0002] Esophageal stricture mainly refers to the narrowing of the esophageal lumen caused by diseases of the esophagus itself or its complications, and is divided into benign and malignant strictures. Benign esophageal stricture is caused by various non-tumor chronic damage and fibrosis of the esophagus, such as accidental ingestion of corrosive substances, radiation damage, anastomotic stricture after esophageal surgery, and gastroesophageal reflux. This can lead to clinical symptoms such as dysphagia, pain during swallowing, weight loss, postprandial regurgitation, nutritional imbalance, and aspiration leading to pneumonia, affecting the patient's quality of life. How to effectively prevent and treat benign esophageal stricture has become an urgent medical challenge.

[0003] In recent years, esophageal stent placement has attracted attention as a safe and effective palliative treatment. For some patients with refractory benign esophageal strictures, when dilation is ineffective, combined treatment with esophageal stent placement can effectively reduce the risk of esophageal stricture, alleviate chronic inflammation and scar tissue remodeling, and maintain esophageal patency. Currently, the types of stents commonly used to treat benign esophageal strictures are self-expanding metal stents or self-expanding plastic stents. These stents may migrate, narrow, or be difficult to remove, thus affecting treatment effectiveness or patient safety. Furthermore, these issues may prevent the stent from being permanently implanted. Therefore, there is an urgent need for a new type of esophageal stent to address these problems. Summary of the Invention

[0004] This invention provides a 4D-printed esophageal stent and its preparation method. The provided 4D-printed esophageal stent has excellent compressive strength and anti-slip ability, and the drug-loaded fiber membrane can prevent esophageal restenosis through long-term uniform and sustained drug release, thereby ensuring the patient's life safety.

[0005] In a first aspect, the present invention provides a 4D-printed esophageal stent, the esophageal stent comprising a stent body and a drug-loaded fiber membrane with a core-shell structure; the stent body is a tubular stent composed of a biomimetic water lily hollow structure; the diameters of the first and last ends of the stent body are both larger than the diameter of the middle section, and the outer surfaces of the first and last ends are provided with barbed structures; the stent body is a biodegradable shape memory polymer; the drug-loaded fiber membrane is located on the outer surface of the middle section of the stent body, and the drug-loaded fiber membrane contains a drug.

[0006] Preferably, the shape memory polymer is prepared by adding polybutylene adipate / terephthalate and tributyl citrate to shape memory polylactic acid.

[0007] More preferably, the amount of poly(butylene adipate) is 2 to 8 wt% of the amount of shape memory polylactic acid, and the amount of tributyl citrate is 9 to 11 wt% of the amount of shape memory polylactic acid.

[0008] Preferably, the outer shell of the drug-loaded fiber membrane is polycaprolactone and the core layer is ethyl cellulose.

[0009] Preferably, the drug-loaded fiber membrane contains an anti-scarring drug.

[0010] More preferably, the content of the anti-scarring drug accounts for 1 to 5 wt% of the core layer of the drug-loaded fiber membrane.

[0011] Preferably, the biomimetic water lily hollow structure uses a regular hexagon as a frame, and the regular hexagon is divided into several rhombuses and several triangles.

[0012] More preferably, the side length of the regular hexagon is 1 / 12 to 1 / 3 of the perimeter of the support body.

[0013] Preferably, the regular hexagon is divided into 10 rhombuses and 4 triangles, and the regular hexagon is an axially symmetric figure.

[0014] Preferably, the acute interior angle of the rhombus is 50° to 70°.

[0015] Preferably, the diameter of the first end is the same as the diameter of the last end, and the diameters of both the first end and the last end are 2 to 4 mm larger than the diameter of the middle section.

[0016] Preferably, the length of the barb structure is 0.5 to 1.5 mm, and the barb angle is 40 to 50°.

[0017] More preferably, 9 to 18 barb structures are provided along the circumference of both the first end and the last end.

[0018] Preferably, the first end and the last end are further provided with developing markers.

[0019] More preferably, the developing marker is one or more of gold, tungsten, platinum-iridium alloy, and nickel-titanium alloy.

[0020] Preferably, the esophageal stent includes an initial shape and a temporary shape, wherein the volume of the initial shape is larger than the volume of the temporary shape; the esophageal stent is deformed from the temporary shape into the initial shape by thermal stimulation.

[0021] In a second aspect, the present invention provides a method for preparing the 4D-printed esophageal stent described in the first aspect above, the method comprising:

[0022] (1) Design a three-dimensional structural model of the esophageal stent;

[0023] (2) Determine the shape memory polymer used in the esophageal stent, make the shape memory polymer into a printing filament, print the printing filament using 4D printing technology, and obtain a stent body with an initial shape after molding;

[0024] (3) A drug-loaded fiber membrane with a core-shell structure was prepared by electrospinning and placed on the outer surface of the middle section of the main body of the stent to obtain the 4D printed esophageal stent.

[0025] Preferably, in step (2), polybutylene adipate / terephthalate, shape memory polylactic acid and tributyl citrate are added to a screw extruder, mixed and extruded to obtain the printed wire.

[0026] More preferably, the screw extruder has a speed of 62-65 rpm and a temperature of 170-180°C.

[0027] Preferably, in step (3), polycaprolactone and a mixed solvent are mixed to obtain a shell spinning solution; ethyl cellulose, an anti-scarring drug, and a mixed solvent are mixed to obtain a core spinning solution; the shell spinning solution and the core spinning solution are respectively added to a syringe, and the drug-loaded fiber membrane is obtained by electrospinning through a coaxial needle; wherein the mixed solvent includes dichloromethane and dimethylacetamide.

[0028] More preferably, the conditions for electrospinning are as follows: the flow rate of the shell spinning solution is 0.6-0.8 mL / h, the flow rate of the core spinning solution is 0.3-0.4 mL / h, the spinning voltage is 18-24 kV, and the spinning distance is 10-20 cm.

[0029] Compared with the prior art, the present invention has at least the following beneficial effects:

[0030] (1) The main body of the 4D-printed esophageal stent provided by the present invention adopts a biomimetic water lily hollow structure, which is designed with reference to the radial distribution of the veins of the water lily leaf, thereby effectively dispersing the pressure on the stent and improving the stent's compressive strength. In addition, the main body of the stent is a dumbbell-shaped structure with thicker ends and thinner middle, and the outer surface of the first and last ends has barbed structure, which effectively improves the anti-slip performance of the esophageal stent.

[0031] (2) The main material of the 4D-printed esophageal stent provided by this invention is composed of shape memory polylactic acid, tributyl citrate, and polybutylene adipate / terephthalate. The addition of tributyl citrate adjusts the glass transition temperature of the material system, making its deformation temperature more suitable for human body temperature, and improves the poor compatibility between shape memory polylactic acid and polybutylene adipate / terephthalate. The combined effect of polybutylene adipate / terephthalate and tributyl citrate effectively improves the toughness and printing performance of the material system, making the mechanical properties of the material system more compatible with the human body and reducing wear on the affected area. In addition, the material system gives the 4D-printed esophageal stent shape memory function, which helps in the minimally invasive implantation of the esophageal stent and reduces patient pain.

[0032] (3) The present invention uses a core-shell structured drug-loaded fiber membrane, with the shell layer being polycaprolactone and the core layer being ethyl cellulose, containing an anti-scarring drug. The presence of the core-shell structure enables the drug in the fiber membrane to be released evenly and continuously over a long period of time, thereby ensuring that the anti-scarring drug can continue to work during the use of the esophageal stent to prevent esophageal restenosis.

[0033] (4) The two ends of the stent body of the present invention are also equipped with metal wires with imaging function, which can prevent the stent from being misplaced or shifted, and can monitor the position of the stent at any time during use, and can detect whether the stent has slipped in time. Attached Figure Description

[0034] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0035] Figure 1 This is a schematic diagram of the initial shape of a 4D-printed esophageal stent provided in an embodiment of the present invention;

[0036] Figure 2 This is a schematic diagram of a biomimetic water lily hollow structure provided in an embodiment of the present invention;

[0037] Figure 3 This is a schematic diagram of the shape recovery of a 4D-printed esophageal stent according to an embodiment of the present invention;

[0038] Figure 4 This is a DSC curve of shape memory polylactic acid with different amounts of tributyl citrate provided in the embodiments of the present invention;

[0039] Figure 5These are DSC curves of shape memory polymers with different poly(adipate adipate) / butyl terephthalate (PET) contents provided in the embodiments of the present invention.

[0040] Figure 6 These are stress-strain diagrams of shape memory polymers with different poly(adipate adipate) / butyl terephthalate (PET) contents provided in the embodiments of the present invention.

[0041] Figure 7 This is a stress-strain comparison diagram of the shape memory polymer provided in Embodiment 1 and Comparative Example 2 of the present invention;

[0042] Figure 8 This is a SEM image of the shape memory polymer provided in Comparative Example 2 of the present invention;

[0043] Figure 9 This is a SEM image of the shape memory polymer provided in Embodiment 1 of the present invention;

[0044] Figure label:

[0045] 100 - Head; 102 - End; 104 - Middle section; 106 - Barbed structure. Detailed Implementation

[0046] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are some embodiments of the present invention, but not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0047] This invention provides a 4D-printed esophageal stent, such as... Figure 1 As shown, the scaffold includes a scaffold body and a drug-loaded fiber membrane with a core-shell structure. The scaffold body is a tubular scaffold composed of a biomimetic water lily hollow structure. The diameters of the first end 100 and the last end 102 of the scaffold body are both larger than the diameter of the middle section 104, and the outer surfaces of the first end 100 and the last end 102 are provided with barbed structures 106. The scaffold body is a biodegradable shape memory polymer. The drug-loaded fiber membrane is located on the outer surface of the middle section 104 of the scaffold body, and contains drugs.

[0048] In this embodiment of the invention, the stent body adopts a biomimetic water lily hollow structure, designed with reference to the radially distributed vein structure of a water lily leaf, thereby effectively dispersing the pressure on the stent and improving its compressive strength. Furthermore, the stent body has an overall dumbbell-shaped structure, thicker at both ends and thinner in the middle, with barbs on the outer surfaces of the first and last ends, effectively improving the anti-slip performance of the esophageal stent. Simultaneously, the drug-loaded fiber membrane contains medication, which can further prevent esophageal restenosis through long-term, uniform, and sustained drug release, thereby ensuring the patient's safety.

[0049] According to some preferred embodiments, shape memory polymers are prepared by adding polybutylene adipate / terephthalate and tributyl citrate to shape memory polylactic acid.

[0050] According to some more preferred embodiments, the amount of poly(butylene adipate) is 2 to 8 wt% of the amount of shape memory polylactic acid (e.g., 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, or 8 wt%), and the amount of tributyl citrate is 9 to 11 wt% of the amount of shape memory polylactic acid (e.g., 9 wt%, 9.5 wt%, 10 wt%, 10.5 wt%, or 11 wt%).

[0051] In this embodiment of the invention, the addition of poly(adipate adipate / butyl terephthalate) within the aforementioned range can improve the toughness and printing performance of the material system. However, the compatibility between shape memory polylactic acid (PLA) and PLA is poor, and the improvement in material performance is not significant. Therefore, tributyl citrate within the aforementioned range is also added. By introducing tributyl citrate, the compatibility between PLA and PLA is improved, thereby effectively improving the toughness and printing performance of the material system, making the mechanical properties of the material system more compatible with the human body, reducing wear on the affected area; and further reducing the glass transition temperature of shape memory PLA, making its deformation temperature more suitable for human body temperature. Experiments have shown that if the content of PLA is less than 2 wt% of the amount of shape memory PLA, the toughness of the material system will be poor; however, if it is more than 8 wt% of the amount of shape memory PLA, the compatibility between shape memory PLA and PLA will be even worse. If the amount of tributyl citrate is less than 9 wt% of shape memory polylactic acid, the compatibility improvement between polylactic acid and poly(adipate adipate / butyl terephthalate) is weak, and the glass transition temperature of the material system is higher than the temperature that the human body can tolerate. If it is higher than 11 wt% of shape memory polylactic acid, although it can significantly improve the compatibility between polylactic acid and poly(adipate adipate / butyl terephthalate), the glass transition temperature of the material system is low, lower than the human body temperature.

[0052] According to some preferred embodiments, the esophageal stent includes an initial shape and a temporary shape, the volume of the initial shape being larger than the volume of the temporary shape; the esophageal stent is deformed from the temporary shape into the initial shape by thermally driven stimulation.

[0053] It should be noted that the thermally driven stimulation temperature of the esophageal stent in this invention is the glass transition temperature of the shape memory polymer. Specifically, the esophageal stent deforms into a temporary shape at the material transition temperature and returns to its initial shape under driving conditions.

[0054] According to some preferred embodiments, the outer shell of the drug-loaded fiber membrane is polycaprolactone and the core layer is ethyl cellulose.

[0055] In this embodiment of the invention, both the stent body and the drug-loaded fiber membrane are made of biodegradable materials, which are biocompatible and can reduce the occurrence of rejection reactions, effectively alleviating the patient's pain. The esophageal stent has a three-dimensional mesh structure, which plays a supporting role at the narrowing of the patient's esophagus after implantation, maintaining the patency of the esophagus and maintaining its normal function. During the use of the esophageal stent, the esophageal stent will be gradually biodegraded into non-toxic and non-immunogenic products, which are absorbed or excreted by the human body, making it safer.

[0056] According to some preferred embodiments, the drug-loaded fiber membrane contains an anti-scarring drug.

[0057] According to some preferred embodiments, the content of the anti-scarring drug accounts for 1 to 5 wt% of the core layer of the drug-loaded fiber membrane (e.g., 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, or 5 wt%).

[0058] According to some preferred embodiments, the anti-scarring drug is paclitaxel.

[0059] In this embodiment of the invention, the presence of the core-shell structure of the drug-loaded fiber membrane enables the drug in the fiber membrane to be released evenly and continuously over a long period of time, thereby ensuring that the anti-scarring drug can continue to work during the use of the esophageal stent to prevent esophageal restenosis.

[0060] In this invention, experiments have shown that if the content of the anti-scarring drug is less than 1 wt% of the core layer of the drug-loaded fiber membrane, the drug dosage is too low, the drug-loaded fiber membrane with the core-shell structure carries too little drug, and the therapeutic effect is reduced; however, if the content of the anti-scarring drug is higher than 5 wt% of the core layer of the drug-loaded fiber membrane, the drug content in the drug-loaded fiber membrane is too high, which may increase the risk of side effects, or even cause local tissue damage or more serious complications.

[0061] According to some preferred embodiments, the biomimetic water lily hollow structure uses a regular hexagon as a frame, and the regular hexagon is divided into several rhombuses and several triangles.

[0062] In this embodiment of the invention, the hexagonal frame is designed with reference to the radially distributed vein structure of a water lily. The vein structure divides the hexagon into several rhombuses and several triangles, thereby effectively dispersing the pressure on the main body of the support and improving the pressure resistance of the main body of the support.

[0063] According to some more preferred embodiments, such as Figure 2 As shown, a regular hexagon is divided into 10 rhombuses and 4 triangles, and the regular hexagon is axially symmetric. Specifically, with the center point of the regular hexagon as the center, 6 identical rhombuses (including the first rhombus, second rhombus, third rhombus, fourth rhombus, fifth rhombus, and sixth rhombus) are arranged, and the 6 acute angles of the 6 rhombuses converge at the center and equally bisect the 360° circumference. A seventh rhombus is placed between the first and second rhombuses, and an eighth rhombus is placed between the second and third rhombuses; a first triangle and a second triangle are placed between the third and fourth rhombuses, and the first and second triangles combine to form a rhombus; a ninth rhombus is placed between the fourth and fifth rhombuses, and a tenth rhombus is placed between the fifth and sixth rhombuses; a third triangle and a fourth triangle are placed between the sixth rhombus and the first rhombus, and the third and fourth triangles combine to form a rhombus; all rhombuses are the same size.

[0064] According to some preferred embodiments, the side length of the regular hexagon is 1 / 12 to 1 / 3 of the perimeter of the support body (for example, it can be 1 / 12, 1 / 11, 1 / 10, 1 / 9, 1 / 8, 1 / 7, 1 / 6, 1 / 5, 1 / 4 or 1 / 3).

[0065] According to some preferred embodiments, the side length of the regular hexagon is 1 / 9 or 1 / 6 of the perimeter of the support body.

[0066] In this invention, experiments have shown that if the side length of the biomimetic water lily hollow structure is less than 1 / 12 of the perimeter of the support body, the biomimetic water lily hollow structure in the support body is too dense, which will increase the difficulty of 4D printing; if the side length of the biomimetic water lily hollow structure is greater than 1 / 3 of the perimeter of the support body, the number of biomimetic water lily hollow structures in the support body is too small, which will lead to poor load-bearing performance of the support body and affect the performance of the esophageal stent.

[0067] According to some preferred embodiments, the acute interior angle of the rhombus is 50° to 70° (for example, it can be 50°, 52°, 55°, 58°, 60°, 62°, 65°, 68° or 70°).

[0068] In this invention, experiments have shown that if the acute interior angle of the rhombus is less than 50°, it will increase the difficulty of 4D printing; if the acute interior angle of the rhombus is greater than 70°, it will reduce the support effect of the curved section of the esophageal stent when it is bent.

[0069] According to some preferred embodiments, the diameter of the first end is the same as the diameter of the last end, and the diameters of both the first and last ends are 2 to 4 mm larger than the diameter of the middle section (for example, 2 mm, 2.5 mm, 3 mm, 3.5 mm or 4 mm).

[0070] According to some preferred embodiments, such as Figure 1 As shown, the length of the barb structure 106 is 0.5 to 1.5 mm (e.g., it can be 0.5 mm, 1 mm or 1.5 mm), and the barb angle α is 40 to 50° (e.g., it can be 40°, 42°, 45°, 48° or 50°).

[0071] According to some preferred embodiments, 9 to 18 (for example, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18) barb structures are provided along the circumference of both the head and the tail.

[0072] In this embodiment of the invention, the radius of the middle section of the stent body is similar to the radius of the diseased esophagus to which the stent body is applied. The diameters of the first and last ends are both larger than the diameter of the middle section, making the stent body dumbbell-shaped. Simultaneously, the radius of the flared ends (i.e., the first and last ends) is 1-2 mm larger than that of the middle section. The outer surface of the flared ends has a barbed structure with a barb length of 0.5-1.5 mm, a barb angle of 40-50°, and 9-18 barbs per ring. The presence of the flared ends and the barb structure effectively improves the anti-slip performance of the stent without damaging the patient's esophagus. It should be noted that the transition section connecting the two ends and the middle section is not specifically limited, as long as it enables the connection. It should be noted that the barb length refers to the length along the longest direction of the barb; the barb angle refers to the angle formed by the line connecting the installation position of the barb on the first and last ends and the barb tip, and the horizontal direction.

[0073] According to some preferred embodiments, the first and last ends are also provided with developing markers.

[0074] According to some preferred embodiments, the developing marker is one or more of gold, tungsten, platinum-iridium alloy, and nickel-titanium alloy.

[0075] In this embodiment of the invention, imaging markers are also provided at both ends of the stent body, such as metal wires made of one or more of gold, tungsten, platinum-iridium alloy, and nickel-titanium alloy. The metal wires are wrapped around both ends of the stent body 2 to 4 times. The presence of imaging markers can prevent the esophageal stent from being misplaced or shifted, and can monitor the position of the esophageal stent at any time during use, and can detect whether the esophageal stent has slipped in a timely manner.

[0076] It should be noted that "one or more" means any one or more of them mixed in any proportion.

[0077] The present invention also provides a method for preparing the above-mentioned 4D-printed esophageal stent, the method comprising:

[0078] (1) Design a three-dimensional structural model of the esophageal stent;

[0079] (2) Determine the shape memory polymer used for the esophageal stent, make the shape memory polymer into printing filaments, use 4D printing technology to print the printing filaments, and obtain the stent body with the initial shape after molding.

[0080] (3) A drug-loaded fiber membrane with a core-shell structure was prepared by electrospinning and placed on the outer surface of the middle section of the stent body to obtain a 4D printed esophageal stent.

[0081] It should be noted that the three-dimensional structural model of the 4D-printed esophageal stent is created by preoperatively collecting medical imaging data of the patient's esophagus and surrounding tissues using technologies such as 3D human scanners, magnetic resonance imaging (MRI), and CT scans. This data is then processed using medical simulation software and computer-aided design software to design and build the stent. This allows the esophageal stent, returning to its initial shape, to provide better support and drug delivery to the patient's esophagus. For example, suitable material systems, structural parameters, and printing methods are selected based on the patient's specific condition, and a three-dimensional structural model of the esophageal stent is then established.

[0082] According to some preferred embodiments, in step (2), polybutylene adipate / terephthalate, shape memory polylactic acid and tributyl citrate are added to a screw extruder, mixed and extruded to obtain a printed wire.

[0083] According to some preferred embodiments, in order to successfully extrude the shape memory polymer and obtain the printed filament, the screw extruder speed is set to 62-65 rpm (e.g., 62 rpm, 63 rpm, 64 rpm or 65 rpm), the die head temperature is set to 170-180°C (e.g., 170°C, 175°C or 180°C), the feed rate is set to 5.1-5.3, and the tributyl citrate feeding rate is set to 2.8-3.2 mL / min.

[0084] Specifically, the 4D printing method for esophageal stents is fused deposition modeling (FDM). The 4D printing method for esophageal stents provided by this invention utilizes 4D printing technology to fabricate esophageal stents, which is not limited by complex structures, is suitable for personalized customization of esophageal stents, and has broad application prospects. Furthermore, it features rapid prototyping, significantly shortening the preparation time of esophageal stent molds, resulting in lower manufacturing costs, a simpler manufacturing method, strong practicality, and easy consumer acceptance, thus demonstrating significant social and economic benefits.

[0085] According to some preferred embodiments, in step (3), polycaprolactone and mixed solvent are mixed to obtain shell spinning solution; ethyl cellulose, anti-scarring drug and mixed solvent are mixed to obtain core spinning solution; the shell spinning solution and core spinning solution are added to syringes respectively, and drug-loaded fiber membrane is obtained by electrospinning through a coaxial needle; wherein, the mixed solvent includes dichloromethane and dimethylacetamide.

[0086] According to some preferred embodiments, the electrospinning conditions are as follows: the flow rate of the shell spinning solution is 0.6 to 0.8 mL / h (e.g., 0.6 mL / h, 0.65 mL / h, 0.7 mL / h, 0.75 mL / h, or 0.8 mL / h), the flow rate of the core spinning solution is 0.3 to 0.4 mL / h (e.g., 0.3 mL / h, 0.35 mL / h, or 0.4 mL / h), the spinning voltage is 18 to 24 kV (e.g., 18 kV, 20 kV, 22 kV, or 24 kV), and the spinning distance is 10 to 20 cm (e.g., 10 cm, 12 cm, 15 cm, 18 cm, or 20 cm).

[0087] In this embodiment of the invention, adding an anti-scarring drug to the core layer can slow down the drug diffusion rate. Simultaneously, by limiting the flow rates of the shell spinning solution and the core spinning solution within the aforementioned range, not only can the continuity of the core-shell structure be maintained and structural defects avoided, but the controllability of the release of the anti-scarring drug within the core layer can also be ensured.

[0088] In this invention, in practical applications, the 4D-printed esophageal stent is shaped into a smaller temporary shape at the glass transition temperature. After being implanted into the human body in this temporary shape, the mesh structure of the esophageal stent is restored to its initial shape by driving conditions, thus providing support.

[0089] To more clearly illustrate the technical solution and advantages of the present invention, the following describes in detail a 4D printed esophageal stent and its preparation method through several embodiments.

[0090] In the following examples and comparative examples, the electrospinning conditions were as follows: the flow rate of the shell spinning solution was 0.8 mL / h, the flow rate of the core spinning solution was 0.4 mL / h, the spinning voltage was 20 kV, and the spinning distance was 12 cm. The relative molecular mass of shape memory polylactic acid was 43,000, the relative molecular mass of poly(butylene adipate / terephthalate) was 150,000, and the relative molecular mass of polycaprolactone was 8,000. The twin-screw extruder speed was 62–65 rpm, the die temperature was 170–180 °C, the feed rate was 5.1–5.3, and the feed rate of tributyl citrate was 2.8–3.2 mL / min.

[0091] Example 1

[0092] The fabrication methods for 4D-printed esophageal stents include:

[0093] S1. Select the material system, structural parameters, and printing method according to the patient's actual condition, and establish a three-dimensional structural model of the esophageal stent based on the size and shape of the corresponding esophagus, such as... Figure 1 and Figure 2 As shown, the hexagonal frame used in the biomimetic water lily hollow structure has a side length of 1 / 6 of the circumference of the main support body. The radius of the flared ends is 1.5mm larger than that of the middle section. The barb length is 1.5mm, the barb angle α is 45°, and there are two rings of barbs at the beginning and end. The number of barbs in each ring is 18.

[0094] S2. The determined shape memory polymer system is made into printing filaments using a twin-screw extruder. Specifically, polybutylene adipate / terephthalate, shape memory polylactic acid, and tributyl citrate are added to the screw extruder, mixed, and extruded to obtain printing filaments. A customized 4D printing scaffold body is then prepared according to the three-dimensional structural model determined in step S1. The amount of polybutylene adipate / terephthalate is 4 wt% of the amount of shape memory polylactic acid, and the amount of tributyl citrate is 10 wt% of the amount of shape memory polylactic acid.

[0095] S3. Dichloromethane and dimethylacetamide are mixed to prepare a mixed solvent. Polycaprolactone is mixed with the mixed solvent to prepare a shell spinning solution. Ethyl cellulose, paclitaxel and the mixed solvent are mixed to prepare a core spinning solution. The shell spinning solution and the core spinning solution are added to a syringe respectively. The drug-loaded fiber membrane with a core-shell structure is obtained by electrospinning through a coaxial needle. The paclitaxel content in the drug-loaded core-shell fiber membrane is 5 wt%.

[0096] A drug-loaded fiber membrane with a core-shell structure is adhered to the outer surface of the middle section of the customized 4D printed scaffold body prepared by the material determined in step S2, and two rings of platinum-iridium alloy metal wires are arranged at the hollowed-out parts at the beginning and end to obtain a customized esophageal scaffold with an initial shape.

[0097] Applications of esophageal stents: Esophageal stents are shaped into a temporary form at the glass transition temperature. After implantation, appropriate actuation conditions allow the stent to return to its initial shape at the affected site, providing support for the narrowed lumen, maintaining its patency, and preserving its normal function. Furthermore, the drug-loaded fiber membrane with a core-shell structure slowly releases medication during stent use, further preventing esophageal restenosis.

[0098] Specifically, regarding the application of esophageal stents, Figure 3 The diagram illustrates the shape changes of the esophageal stent, from left to right: the temporary shape and the initial shape of the esophageal stent. (The text then repeats itself, seemingly incomplete.) Figure 1 After shaping the esophageal stent to its initial shape, the stent is heated to its glass transition temperature and shaped accordingly. An external force is applied and held for 5–10 seconds until the stent cools to room temperature. The temporary shape of the esophageal stent can be designed to be small and easily implanted minimally invasively. After implantation, it deforms and returns to its preset three-dimensional shape, i.e., the initial shape, thus providing feasibility for minimally invasive surgical implantation of esophageal stents.

[0099] Example 2

[0100] The fabrication methods for 4D-printed esophageal stents include:

[0101] S1. Select the material system, structural parameters, and printing method according to the patient's actual condition, and establish a three-dimensional structural model of the esophageal stent based on the size and shape of the corresponding esophagus, such as... Figure 1 and Figure 2 As shown, the hexagonal frame used in the biomimetic water lily hollow structure has a side length of 1 / 9 of the circumference of the main support body. The radius of the flared ends is 1.5mm larger than that of the middle section. The barb length is 1.5mm, the barb angle α is 45°, and there are two rings of barbs at the beginning and end. The number of barbs in each ring is 18.

[0102] S2. The determined shape memory polymer system is made into printing filaments using a twin-screw extruder. Specifically, poly(butylene adipate / terephthalate) shape memory polylactic acid and tributyl citrate are added to the screw extruder, mixed, and extruded to obtain printing filaments. A customized 4D printing scaffold body is prepared according to the three-dimensional structural model determined in step S1. The amount of poly(butylene adipate / terephthalate) is 2 wt% of the amount of shape memory polylactic acid, and the amount of tributyl citrate is 9 wt% of the amount of shape memory polylactic acid.

[0103] S3. Dichloromethane and dimethylacetamide are mixed to prepare a mixed solvent. Polycaprolactone is mixed with the mixed solvent to prepare a shell spinning solution. Ethyl cellulose, paclitaxel and the mixed solvent are mixed to prepare a core spinning solution. The shell spinning solution and the core spinning solution are added to a syringe respectively. The drug-loaded fiber membrane with a core-shell structure is obtained by electrospinning through a coaxial needle. The paclitaxel content in the drug-loaded core-shell fiber membrane is 5 wt%.

[0104] A drug-loaded fiber membrane with a core-shell structure is adhered to the outer surface of the middle section of the customized 4D printed scaffold body prepared by the material determined in step S2, and two rings of platinum-iridium alloy metal wires are arranged at the hollowed-out parts at the beginning and end to obtain a customized esophageal scaffold with an initial shape.

[0105] Example 3

[0106] The fabrication methods for 4D-printed esophageal stents include:

[0107] S1. Select the material system, structural parameters, and printing method according to the patient's actual condition, and establish a three-dimensional structural model of the esophageal stent based on the size and shape of the corresponding esophagus, such as... Figure 1 and Figure 2 As shown, the hexagonal frame used in the biomimetic water lily hollow structure has a side length of 1 / 6 of the circumference of the main support body. The radius of the flared ends is 1.5mm larger than that of the middle section. The barb length is 1.5mm, the barb angle α is 50°, and there are two rings of barbs at the beginning and end. The number of barbs in each ring is 18.

[0108] S2. The determined shape memory polymer system is made into printing filaments using a twin-screw extruder. Specifically, polybutylene adipate / terephthalate, shape memory polylactic acid, and tributyl citrate are added to the screw extruder, mixed, and extruded to obtain printing filaments. A customized 4D printing scaffold body is then prepared according to the three-dimensional structural model determined in step S1. The amount of polybutylene adipate / terephthalate is 6 wt% of the amount of shape memory polylactic acid, and the amount of tributyl citrate is 10 wt% of the amount of shape memory polylactic acid.

[0109] S3. Dichloromethane and dimethylacetamide are mixed to prepare a mixed solvent. Polycaprolactone is mixed with the mixed solvent to prepare a shell spinning solution. Ethyl cellulose, paclitaxel and the mixed solvent are mixed to prepare a core spinning solution. The shell spinning solution and the core spinning solution are added to a syringe respectively. The drug-loaded fiber membrane with a core-shell structure is obtained by electrospinning through a coaxial needle. The paclitaxel content in the drug-loaded core-shell fiber membrane is 5 wt%.

[0110] A drug-loaded fiber membrane with a core-shell structure is adhered to the outer surface of the middle section of the customized 4D printed scaffold body prepared by the material determined in step S2, and two rings of platinum-iridium alloy metal wires are arranged at the hollowed-out parts at the beginning and end to obtain a customized esophageal scaffold with an initial shape.

[0111] Example 4

[0112] The fabrication methods for 4D-printed esophageal stents include:

[0113] S1. Select the material system, structural parameters, and printing method according to the patient's actual condition, and establish a three-dimensional structural model of the esophageal stent based on the size and shape of the corresponding esophagus, such as... Figure 1 and Figure 2 As shown, the hexagonal frame used in the biomimetic water lily hollow structure has a side length of 1 / 6 of the perimeter of the main support body. The radius of the flared ends is 1mm larger than that of the middle section. The barb length is 1mm, the barb angle α is 50°, and there are two rings of barbs at the beginning and end. The number of barbs in each ring is 18.

[0114] S2. The determined shape memory polymer system is made into printing filaments using a twin-screw extruder. Specifically, polybutylene adipate / terephthalate, shape memory polylactic acid, and tributyl citrate are added to the screw extruder, mixed, and extruded to obtain printing filaments. A customized 4D printing scaffold body is then prepared according to the three-dimensional structural model determined in step S1. The amount of polybutylene adipate / terephthalate is 8 wt% of the amount of shape memory polylactic acid, and the amount of tributyl citrate is 11 wt% of the amount of shape memory polylactic acid.

[0115] S3. Dichloromethane and dimethylacetamide are mixed to prepare a mixed solvent. Polycaprolactone is mixed with the mixed solvent to prepare a shell spinning solution. Ethyl cellulose, paclitaxel and the mixed solvent are mixed to prepare a core spinning solution. The shell spinning solution and the core spinning solution are added to a syringe respectively. The drug-loaded fiber membrane with a core-shell structure is obtained by electrospinning through a coaxial needle. The paclitaxel content in the drug-loaded core-shell fiber membrane is 5 wt%.

[0116] A drug-loaded fiber membrane with a core-shell structure is adhered to the outer surface of the middle section of the customized 4D printed scaffold body prepared by the material determined in step S2, and two rings of platinum-iridium alloy metal wires are arranged at the hollowed-out parts at the beginning and end to obtain a customized esophageal scaffold with an initial shape.

[0117] Example 5

[0118] The fabrication methods for 4D-printed esophageal stents include:

[0119] S1. Select the material system, structural parameters, and printing method according to the patient's actual condition, and establish a three-dimensional structural model of the esophageal stent based on the size and shape of the corresponding esophagus, such as... Figure 1 and Figure 2 As shown, the hexagonal frame used in the biomimetic water lily hollow structure has a side length of 1 / 6 of the circumference of the main support body. The radius of the flared ends is 1.5mm larger than that of the middle section. The barb length is 1.5mm, the barb angle α is 45°, and there are two rings of barbs at both the beginning and end. The number of barbs in each ring is 12.

[0120] S2. The determined shape memory polymer system is made into printing filaments using a twin-screw extruder. Specifically, polybutylene adipate / terephthalate, shape memory polylactic acid, and tributyl citrate are added to the screw extruder, mixed, and extruded to obtain printing filaments. A customized 4D printing scaffold body is then prepared according to the three-dimensional structural model determined in step S1. The amount of polybutylene adipate / terephthalate is 4 wt% of the amount of shape memory polylactic acid, and the amount of tributyl citrate is 10 wt% of the amount of shape memory polylactic acid.

[0121] S3. Dichloromethane and dimethylacetamide are mixed to prepare a mixed solvent. Polycaprolactone is mixed with the mixed solvent to prepare a shell spinning solution. Ethyl cellulose, paclitaxel and the mixed solvent are mixed to prepare a core spinning solution. The shell spinning solution and the core spinning solution are added to a syringe respectively. The drug-loaded fiber membrane with a core-shell structure is obtained by electrospinning through a coaxial needle. The paclitaxel content in the drug-loaded core-shell fiber membrane is 1 wt%.

[0122] A drug-loaded fiber membrane with a core-shell structure is adhered to the outer surface of the middle section of the customized 4D printed scaffold body prepared by the material determined in step S2, and two rings of platinum-iridium alloy metal wires are arranged at the hollowed-out parts at the beginning and end to obtain a customized esophageal scaffold with an initial shape.

[0123] Example 6

[0124] Example 6 is basically the same as Example 1, except that the content of poly(butylene adipate) / poly(terephthalate) in step S2 is different.

[0125] Specifically, the amount of poly(dibutyl adipate) is 2 wt% of the amount of shape memory polylactic acid, and the amount of tributyl citrate is 10 wt% of the amount of shape memory polylactic acid.

[0126] Example 7

[0127] Example 7 is basically the same as Example 1, except that the content of poly(butylene adipate) / poly(terephthalate) in step S2 is different.

[0128] Specifically, the amount of poly(butylene adipate) is 8 wt% of the amount of shape memory polylactic acid, and the amount of tributyl citrate is 10 wt% of the amount of shape memory polylactic acid.

[0129] Comparative Example 1

[0130] Comparative Example 1 is basically the same as Example 1, except that poly(butylene adipate) was not added in step S2.

[0131] Comparative Example 2

[0132] Comparative Example 2 is basically the same as Example 1, except that tributyl citrate was not added in step S2.

[0133] Figure 4 The DSC curves of shape memory polylactic acid with different amounts of tributyl citrate are shown. Figure 4 It is known that when the tributyl citrate content is between 9 wt% and 11 wt% of shape memory polylactic acid (PLA), the glass transition temperature of PLA with added tributyl citrate is between 38.2℃ and 44.7℃. However, when the tributyl citrate content is 8 wt% of PLA, the glass transition temperature of this system is 47.8℃, exceeding the temperature that the human body can withstand. When the tributyl citrate content is 12 wt% of PLA, the glass transition temperature of this system is as low as 34.3℃, below the human body temperature. Since the stent will return to its initial shape after being inserted into the body, there may be a problem of the esophageal stent returning to its initial shape in non-affected areas. It should be noted that... Figure 4 PLA / x%TBC in the text indicates shape memory polylactic acid with xwt% added tributyl citrate, where the tributyl citrate content is xwt% of shape memory polylactic acid.

[0134] Figure 5 DSC curves of shape memory polymers with different poly(adipate adipate) / butyl terephthalate (PET) contents are shown for comparison. Figure 4 and Figure 5 It can be seen that the introduction of poly(adipic acid) / butylene terephthalate did not change the glass transition temperature of the system, and moreover, due to Figure 5 It can be seen that the content of poly(dibutyl terephthalate) has little effect on shape memory polymers, and the glass transition temperature of shape memory polymers is around 40℃, which is closer to human body temperature.

[0135] Figure 6 Stress-strain curves of shape memory polymers with different poly(adipate adipate) / butyl terephthalate (PET) contents are shown. Figure 6It is known that the introduction of poly(adipate adipate / butyl terephthalate) improves the toughness of shape memory polylactic acid. When the amount of poly(adipate adipate / butyl terephthalate) is 2 to 8 wt% of the amount of shape memory polylactic acid, the shape memory polymer has excellent toughness.

[0136] Figure 7 The stress-strain curves of the shape memory polymers provided in Example 1 and Comparative Example 2 are shown. By comparison, it can be seen that the addition of tributyl citrate improves the compatibility of shape memory polylactic acid with poly(adipic acid / butyl terephthalate).

[0137] Figure 8 , Figure 9 SEM images of the shape memory polymers in Comparative Example 2 and Example 1 are shown respectively. Figure 8 It is known that shape memory polylactic acid (PLA) is incompatible with poly(butylene adipate / terephthalate); Figure 9 It can be seen that the addition of tributyl citrate improves the compatibility of shape memory polylactic acid with poly(adipic acid / butyl terephthalate).

[0138] The radial support force of the 4D-printed esophageal stent prepared in Example 1 was tested at various temperatures. The results showed that the radial support force of the 4D-printed esophageal stent was 2.113 N / mm at room temperature (25℃), 0.821 N / mm at 36℃, 0.74 N / mm at 37℃, 0.476 N / mm at 38℃, 0.444 N / mm at 39℃, and 0.334 N / mm at 40℃. The radial support force is the force required to compress the stent to 50% of its initial diameter. The glass transition temperature of this 4D-printed esophageal stent is 41.8℃.

[0139] Based on existing stents described in the 2016 American Journal of Translational Research article, "A novel biodegradable esophageal stent: results from mechanical and animal experiments" by Liu J, Shang L, Liu J et al., it can be found that the radial support force of the wall stent is 0.172 N / mm, the radial support force of the ZA stent is 0.095 N / mm, the radial support force of the Accucflex stent is 0.065 N / mm, the radial support force of the SMART stent is 0.093 N / mm, the radial support force of the spiral Z-shaped stent is 0.112 N / mm, and the radial support force of the NT stent is 0.051 N / mm. All of these are far lower than the 2.113 N / mm of the esophageal stent in Example 1. Therefore, it is further confirmed that the esophageal stent prepared in this application has excellent compressive strength.

[0140] It should be noted that, Figure 5 and Figure 6 The PLA in the example is pure shape memory polylactic acid; PLA / 10%TBC corresponds to the shape memory polymer prepared in Example 1; PLA / 10%TBC / 2%PBAT corresponds to the shape memory polymer prepared in Example 6; PLA / 10%TBC / 4%PBAT corresponds to the shape memory polymer prepared in Example 1; PLA / 10%TBC / 6%PBAT corresponds to the shape memory polymer prepared in Example 3; and PLA / 10%TBC / 8%PBAT corresponds to the shape memory polymer prepared in Example 7. Figure 7 The PLA / 4PBAT corresponds to the shape memory polymer prepared in Example 2, and the PLA / 10TBC / 4PBAT corresponds to the shape memory polymer prepared in Example 1.

[0141] By comparing the applications of the embodiments of this application with those of the 4D-printed esophageal stents in Comparative Examples 1 to 6 above, it can be found that the 4D-printed esophageal stents prepared in the embodiments of this application have excellent compressive strength and anti-slip ability, and the drug-loaded fiber membrane can prevent esophageal restenosis by releasing drugs evenly and continuously over a long period of time, thereby ensuring the safety of patients' lives.

[0142] 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 the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A 4D-printed esophageal stent, characterized in that, The esophageal stent includes a stent body and a drug-loaded fiber membrane with a core-shell structure; the stent body is a tubular stent composed of a biomimetic water lily hollow structure; the diameter of the first and last ends of the stent body is larger than the diameter of the middle section, and the outer surface of the first and last ends is provided with barbed structures; the stent body is a biodegradable shape memory polymer; the drug-loaded fiber membrane is located on the outer surface of the middle section of the stent body, and the drug-loaded fiber membrane contains drugs; The biomimetic water lily hollow structure uses a regular hexagon as a frame, and the regular hexagon is divided into several rhombuses and several triangles; the regular hexagon is an axially symmetric figure; the diameter of the first end is the same as the diameter of the last end, and the diameters of the first end and the last end are both 2-4 mm larger than the diameter of the middle section.

2. The 4D-printed esophageal stent according to claim 1, characterized in that, The shape memory polymer is prepared by adding polybutylene adipate / terephthalate and tributyl citrate to shape memory polylactic acid.

3. The 4D-printed esophageal stent according to claim 2, characterized in that, The amount of poly(dibutyl adipate) / butyl terephthalate is 2-8 wt% of the amount of shape memory polylactic acid, and the amount of tributyl citrate is 9-11 wt% of the amount of shape memory polylactic acid.

4. The 4D-printed esophageal stent according to claim 1, characterized in that, The drug-loaded fiber membrane has a shell layer of polycaprolactone and a core layer of ethyl cellulose; and / or, The drug-loaded fiber membrane contains an anti-scarring drug.

5. The 4D-printed esophageal stent according to claim 4, characterized in that, The content of the anti-scarring drug is 1-5 wt% of the core layer of the drug-loaded fiber membrane.

6. The 4D-printed esophageal stent according to claim 1, characterized in that, The regular hexagon is divided into 10 rhombuses and 4 triangles; and / or, The acute interior angle of the rhombus is 50°~70°.

7. The 4D-printed esophageal stent according to claim 1, characterized in that, The length of the barb structure is 0.5~1.5mm, and the barb angle is 40~50°.

8. The 4D-printed esophageal stent according to claim 1, characterized in that, Nine to eighteen barb structures are provided along the circumference of both the first end and the last end.

9. The 4D-printed esophageal stent according to any one of claims 1 to 8, characterized in that, The first end and the second end are also provided with developing markers.

10. The 4D-printed esophageal stent according to claim 9, characterized in that, The developing marker is one or more of gold, tungsten, platinum-iridium alloy, and nickel-titanium alloy; and / or, The esophageal stent includes an initial shape and a temporary shape, wherein the volume of the initial shape is larger than the volume of the temporary shape; the esophageal stent is deformed from the temporary shape into the initial shape by thermal stimulation.

11. A method for preparing a 4D-printed esophageal stent according to any one of claims 1 to 10, characterized in that, The preparation method includes: (1) Design a three-dimensional structural model of the esophageal stent; (2) Determine the shape memory polymer used in the esophageal stent, make the shape memory polymer into a printing filament, print the printing filament using 4D printing technology, and obtain a stent body with an initial shape after molding; (3) A drug-loaded fiber membrane with a core-shell structure was prepared by electrospinning and placed on the outer surface of the middle section of the main body of the stent to obtain the 4D printed esophageal stent.

12. The preparation method according to claim 11, characterized in that, In step (2), Polybutylene adipate / terephthalate, shape memory polylactic acid, and tributyl citrate are added to a screw extruder, mixed, and extruded to obtain the printed wire.

13. The preparation method according to claim 12, characterized in that, In step (2), The screw extruder has a speed of 62~65 rpm and a temperature of 170~180℃.

14. The preparation method according to claim 11 or 12, characterized in that, In step (3), Polycaprolactone and a mixed solvent are mixed to obtain a shell spinning solution; ethyl cellulose, an anti-scarring drug, and a mixed solvent are mixed to obtain a core spinning solution; the shell spinning solution and the core spinning solution are respectively added to a syringe, and the drug-loaded fiber membrane is obtained by electrospinning through a coaxial needle; wherein, the mixed solvent includes dichloromethane and dimethylacetamide.

15. The preparation method according to claim 14, characterized in that, The conditions for electrospinning are as follows: the flow rate of the shell spinning solution is 0.6~0.8 mL / h, the flow rate of the core spinning solution is 0.3~0.4 mL / h, the spinning voltage is 18~24 kV, and the spinning distance is 10~20 cm.

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