An anti-restenotic shape memory polymer enteric stent and a method of making the same

Abstract

This invention provides an anti-restenosis shape memory polymer intestinal scaffold and its preparation method. The intestinal scaffold includes a tubular scaffold and a drug-loaded layer embedded in the tubular scaffold; both the tubular scaffold and the drug-loaded layer are biodegradable materials; the tubular scaffold is composed of at least two shape memory materials with different driving conditions; the drug-loaded layer includes a drug and a hydrogel; the intestinal scaffold includes an initial shape, an intermediate shape, and a temporary shape; the volume of the initial shape is larger than the volumes of the intermediate and temporary shapes; the volume of the intermediate shape is larger than the volume of the temporary shape; wherein, the intestinal scaffold deforms into different shapes under different driving conditions. The anti-restenosis shape memory polymer intestinal scaffold provided by this invention not only solves the problem of friction with the patient's surgical site and scar after implantation of existing intestinal scaffolds, and even the damage or infection of the intestinal mucosa, but also has anti-restenosis function, which can prevent postoperative restenosis.

Description

Technical Field

[0001] This invention relates to the field of medical material manufacturing technology, and in particular to an anti-restenosis shape memory polymer intestinal stent and its preparation method. Background Technology

[0002] Intestinal stents are commonly used to treat intestinal obstruction, intestinal fistula, and other diseases caused by intestinal cancer. Patients with intestinal cancer generally require intestinal and intestinal tissue resection, and intestinal stents, as intraluminal supports, provide a new option for these patients. However, after implantation of ordinary intestinal stents, discomfort caused by friction with the surgical site and scar can lead to intestinal mucosal damage or infection. Furthermore, some patients may experience intestinal restenosis after stent implantation, thus affecting the therapeutic effect of the intestinal stent and posing potential risks to wound healing and the patient's life. Summary of the Invention

[0003] This invention provides an anti-restenosis shape memory polymer intestinal stent and its preparation method. The provided anti-restenosis shape memory polymer intestinal stent not only solves the problem of friction between existing intestinal stents and the patient's surgical site and scars after implantation, and even causes damage or infection to the intestinal mucosa, but also has anti-restenosis function to better prevent restenosis after intestinal stent surgery and ensure the patient's life safety.

[0004] In a first aspect, the present invention provides an anti-restenosis shape memory polymer intestinal stent, the intestinal stent comprising a tubular stent and a drug-loaded layer embedded in the tubular stent;

[0005] Both the tubular scaffold and the drug-loaded layer are biodegradable materials; the tubular scaffold is composed of at least two shape memory materials with different driving conditions; the drug-loaded layer is composed of drugs and hydrogels.

[0006] The intestinal stent includes an initial shape, an intermediate shape, and a temporary shape; the volume of the initial shape is larger than the volumes of the intermediate shape and the temporary shape; the volume of the intermediate shape is larger than the volume of the temporary shape; wherein the intestinal stent deforms into different shapes under different driving conditions.

[0007] Preferably, the shape memory material is a shape memory polymer or a shape memory polymer containing functional fillers;

[0008] The shape memory polymer is at least one of polyurethane, polyester, polyvinyl alcohol, polyethylene glycol, polycaprolactone, polylactic acid, poly(ethylene glycol) diacrylate, acrylic epoxidized soybean oil, or poly(d,l-lactide-co-trimethylene carbonate).

[0009] The functional filler is a magnetic filler or a photothermal filler.

[0010] Preferably, the intestinal scaffold deforms into the temporary shape at the material transition temperature;

[0011] The intestinal stent deforms from the temporary shape to the intermediate shape under the first driving condition;

[0012] The intestinal stent is deformed from the intermediate shape to the initial shape under the second driving condition; wherein the first driving condition is different from the second driving condition.

[0013] Preferably, the tubular support includes a mesh structure and a negative Poisson's ratio structure; the driving conditions of the mesh structure and the negative Poisson's ratio structure are different, and the negative Poisson's ratio structure is located at the node of the mesh structure.

[0014] Preferably, the shape memory material used in the mesh structure includes at least one of polyurethane, polyester, polyvinyl alcohol, or polyethylene glycol.

[0015] Preferably, the negative Poisson's ratio structure is composed of a shape memory polymer and a functional filler; the functional filler is a magnetic filler or a photothermal filler; the shape memory polymer is at least one of polycaprolactone, polylactic acid, polyurethane, poly(ethylene glycol) diacrylate, acrylic epoxidized soybean oil, or poly(d,l-lactide-co-trimethylene carbonate).

[0016] Preferably, the mass ratio of the shape memory polymer to the functional filler in the negative Poisson's ratio structure is (3-5):1.

[0017] More preferably, the magnetic filler is at least one of γ-ferric oxide, iron tetroxide, neodymium iron boron, carbonyl iron, and nickel-zinc ferrite.

[0018] More preferably, the photothermal filler is at least one of gold nanoparticles, carbon black, graphene oxide, or black phosphorus.

[0019] Preferably, the intestinal scaffold deforms into the temporary shape at the material transition temperature;

[0020] The mesh structure returns to the first initial shape under the first driving condition, causing the intestinal scaffold to deform from the temporary shape to the intermediate shape;

[0021] The negative Poisson's ratio structure returns to the second initial shape under the second driving condition, causing the intestinal scaffold to deform from the intermediate shape to the initial shape.

[0022] Preferably, the hydrogel is at least one of chitosan, cellulose, hyaluronic acid, heparin, alginate, polyacrylic acid, polyethylene glycol, polymethacrylic acid, polyvinyl alcohol, polyacrylamide, or poly(N-isopropylacrylamide) with stress-responsive properties.

[0023] The drug-loaded layer responds to external stimuli to control the drug release rate; the external stimuli include one or more of pH, light, magnetism, temperature, specific ions, or enzymes.

[0024] More preferably, the mass ratio of the drug to the hydrogel is 1:(10-20).

[0025] In a second aspect, the present invention provides a method for preparing the anti-restenosis shape memory polymer intestinal scaffold described in the first aspect above, the method comprising:

[0026] (1) Design a three-dimensional structural model of an intestinal scaffold including a tubular scaffold and a drug-loaded layer;

[0027] (2) Determine the shape memory material used for the tubular scaffold and the drug-loaded layer, and use 4D printing technology to perform multi-material printing to obtain a 4D printed intestinal scaffold with an initial shape after molding.

[0028] Preferably, the drug-loaded layer is composed of a drug and a hydrogel with stress-responsive properties, wherein the mass ratio of the drug to the hydrogel is 1:(10-20).

[0029] Preferably, the tubular support includes a mesh structure and a negative Poisson's ratio structure; the driving conditions of the mesh structure and the negative Poisson's ratio structure are different, and the negative Poisson's ratio structure is located at the node of the mesh structure.

[0030] Compared with the prior art, the present invention has at least the following beneficial effects:

[0031] (1) The anti-restenosis shape memory polymer intestinal stent provided by the present invention is composed of at least two shape memory materials with different driving conditions, so that the intestinal stent can be deformed into different shapes under different driving conditions, and the volume of the initial shape > the volume of the intermediate shape > the volume of the temporary shape. When the intestinal stent is deformed from the temporary shape to the intermediate shape, it plays the function of supporting the intestine as existing intestinal stents. When the intestinal stent is deformed from the temporary shape to the intermediate shape, it can be applied to patients when restenosis occurs in the intestinal lesion, further improving the support effect of the intestinal stent, thereby playing the role of anti-intestinal restenosis, ensuring that the intestinal stent can still play a good therapeutic effect in the face of intestinal restenosis.

[0032] (2) The anti-restenosis shape memory polymer intestinal scaffold provided by this invention has a drug-loaded layer embedded in it. Compared with other drug carriers, the hydrogel has better stability, higher encapsulation effectiveness, better biocompatibility and biodegradability, and can continuously release drugs at the affected site. In addition, for hydrogels with stress-responsive properties, the drug-loaded layer can respond to external stimuli such as pH, light, magnetism, temperature, specific ions or enzymes, thereby further controlling the drug release rate and significantly improving the convenience and efficiency of drug delivery.

[0033] (3) The method for preparing the anti-restenosis shape memory polymer intestinal stent provided by the present invention utilizes 4D printing technology to prepare multi-material shape memory polymer intestinal stents. It is not limited by complex structures, has the characteristics of rapid prototyping, is suitable for personalized customization of intestinal stents, and has a wide range of application prospects. 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 a planar structure of an anti-restenosis shape memory polymer intestinal stent provided in an embodiment of the present invention;

[0036] Figure 2 This is a schematic diagram of a structural unit of an anti-restenosis shape memory polymer intestinal stent provided in an embodiment of the present invention;

[0037] Figure 3 This is a schematic diagram of the temporary shape of an anti-restenosis shape memory polymer intestinal stent provided in an embodiment of the present invention;

[0038] Figure 4 This is a schematic diagram of the intermediate shape of an anti-restenosis shape memory polymer intestinal stent provided in an embodiment of the present invention;

[0039] Figure 5 This is a schematic diagram of the initial shape of an anti-restenosis shape memory polymer intestinal stent provided in an embodiment of the present invention;

[0040] Figure 6 This is a schematic diagram of the shape recovery change of an anti-restenosis shape memory polymer intestinal stent provided in an embodiment of the present invention;

[0041] Figure label:

[0042] 1-Network structure, 2-Negative Poisson's ratio structure, 3-Drug loading layer. Detailed Implementation

[0043] 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.

[0044] This invention provides an anti-restenosis shape memory polymer intestinal stent, the intestinal stent comprising a tubular stent and a drug-loaded layer embedded in the tubular stent;

[0045] Both the tubular scaffold and the drug-loaded layer are biodegradable materials; the tubular scaffold is composed of at least two shape memory materials with different driving conditions; the drug-loaded layer consists of drugs and hydrogels.

[0046] The intestinal scaffold comprises an initial shape, an intermediate shape, and a temporary shape; the volume of the initial shape is larger than the volumes of the intermediate and temporary shapes; the volume of the intermediate shape is larger than the volume of the temporary shape; and the intestinal scaffold deforms into different shapes under different driving conditions.

[0047] In this invention, the anti-restenosis shape memory polymer intestinal stent is composed of at least two shape memory materials with different driving conditions, enabling the intestinal stent to deform into different shapes under different driving conditions, with the volume of the initial shape > the volume of the intermediate shape > the volume of the temporary shape. When the intestinal stent deforms from the temporary shape to the intermediate shape, it performs the function of supporting the intestine as possessed by existing intestinal stents. When the intestinal stent deforms from the temporary shape to the intermediate shape, it can be applied to patients when restenosis occurs in the affected area of ​​the intestine, further improving the support effect of the intestinal stent, thereby playing an anti-restenosis role and ensuring that the intestinal stent can still exert a good therapeutic effect in the face of intestinal restenosis.

[0048] In this invention, a drug-loaded layer is embedded in the anti-restenosis shape memory polymer intestinal scaffold. Compared with other drug carriers, hydrogels have better stability, higher encapsulation effectiveness, better biocompatibility and biodegradability, which can achieve controlled and slow release of drugs at the affected site, achieve targeted treatment, and obtain better therapeutic effects.

[0049] In this invention, the intestinal stent is made of biodegradable material. The biocompatible intestinal stent can reduce the occurrence of rejection reactions after implantation in the human body, effectively alleviating the patient's pain. At the same time, during the intestinal healing time, the intestinal stent will be gradually biodegraded into non-toxic and non-immunogenic products, which are absorbed or excreted by the human body, making it safer.

[0050] It should be noted that the initial, intermediate, and temporary shapes of the anti-restenosis shape memory polymer intestinal scaffold are all three-dimensional mesh-like tubular structures.

[0051] According to some preferred embodiments, the shape memory material is a shape memory polymer or a shape memory polymer containing functional fillers;

[0052] The shape memory polymer is at least one of polyurethane, polyester, polyvinyl alcohol, polyethylene glycol, polycaprolactone, polylactic acid, poly(ethylene glycol) diacrylate, acrylic epoxidized soybean oil, or poly(d,l-lactide-co-trimethylene carbonate).

[0053] The functional fillers are magnetic fillers or photothermal fillers.

[0054] It should be noted that "at least one" means any one or more of them mixed in any proportion.

[0055] According to some preferred embodiments, the intestinal stent deforms into a temporary shape at a material transition temperature;

[0056] Under the first driving condition, the intestinal scaffold deforms from a temporary shape to an intermediate shape;

[0057] Under the second driving condition, the intestinal scaffold deforms from its intermediate shape back to its initial shape.

[0058] It should be noted that the first driving condition is different from the second driving condition. The intestinal stent is shaped into a temporary shape at its glass transition temperature. By compressing the intestinal stent into a small, easily implantable temporary shape, it is implanted into the human body or placed in an environment simulating human body fluids. Under the first driving condition, the intestinal stent can return to its intermediate shape, thus supporting the intestine. Under the second driving condition, the intestinal stent can continue to return to its initial shape, ultimately reaching a preset three-dimensional shape, further supporting the intestine. Thus, in this invention, since the tubular stent is composed of at least two shape memory materials with different driving conditions, the corresponding shape memory materials will deform under different driving conditions. After two driving conditions, the intestinal stent can undergo two deformations: first from the temporary shape to the intermediate shape and then back to the initial shape. Therefore, the problem of restenosis after intestinal stent surgery can be solved through this repeated deformation.

[0059] According to some preferred embodiments, the tubular support includes a mesh structure and a negative Poisson's ratio structure; the driving conditions of the mesh structure and the negative Poisson's ratio structure are different, and the negative Poisson's ratio structure is located at the node of the mesh structure.

[0060] It should be noted that the negative Poisson's ratio structures are all distributed across the mesh structure. In this invention, since the negative Poisson's ratio structures are distributed across the nodes of the mesh structure, when the driving conditions for the negative Poisson's ratio structure are met, the negative Poisson's ratio structure can cause the intestinal stent to have a negative Poisson's ratio effect in both the radial and axial directions, and possess the special mechanical properties of the negative Poisson's ratio structure, that is, when the driving conditions are met after implantation, the intestinal stent expands simultaneously in both the radial and axial dimensions.

[0061] Specifically, negative Poisson ratio structures include, but are not limited to, rotational quadrilateral structural units, concave hexagonal structural units, star-shaped structural units, and double-arrow structural units.

[0062] According to some preferred embodiments, the shape memory material used in the mesh structure includes at least one of polyurethane, polyester, polyvinyl alcohol, or polyethylene glycol.

[0063] According to some preferred embodiments, the negative Poisson's ratio structure is composed of a shape memory polymer and a functional filler; the functional filler is a magnetic filler or a photothermal filler; the shape memory polymer is at least one of polycaprolactone, polylactic acid, polyurethane, poly(ethylene glycol) diacrylate, acrylic epoxidized soybean oil, or poly(d,l-lactide-co-trimethylene carbonate).

[0064] According to some preferred embodiments, the mass ratio of shape memory polymer to functional filler in the negative Poisson's ratio structure is (3 to 5):1 (for example, it can be 3:1, 3.5:1, 4:1, 4.5:1 or 5:1).

[0065] In this invention, experiments have confirmed that if the mass ratio of shape memory polymer to functional filler in the negative Poisson's ratio structure is less than 3:1, the shape memory polymer and functional filler are difficult to disperse evenly and may even agglomerate, making it difficult to prepare a negative Poisson's ratio structure; if the mass ratio of shape memory polymer to functional filler in the negative Poisson's ratio structure is greater than 5:1, the prepared negative Poisson's ratio structure will have poor response and small deformation under the corresponding driving conditions.

[0066] According to some more preferred embodiments, the magnetic filler is at least one selected from γ-ferric oxide, iron tetroxide, neodymium iron boron, carbonyl iron, and nickel-zinc ferrite.

[0067] According to some preferred embodiments, the photothermal filler is at least one of gold nanoparticles, carbon black, graphene oxide, or black phosphorus.

[0068] It should be noted that the particle size of both magnetic fillers and photothermal fillers is less than 20 nm.

[0069] According to some preferred embodiments, the drug-loaded layer is embedded in a mesh structure.

[0070] In this invention, the drug-loaded layer is embedded in the mesh structure of the intestinal scaffold, but not completely replacing that segment of the mesh structure. This allows the mesh structure to serve as a scaffold carrying the drug-loaded layer, preventing the drug-laden hydrogel from easily detaching when the intestinal scaffold deforms. The drug loaded on the drug-loaded layer can alleviate the inflammatory response caused by the implantation of the intestinal scaffold, and simultaneously, the drug can reach the affected area more effectively with the intestinal scaffold, enhancing its efficacy.

[0071] According to some preferred embodiments, the intestinal stent deforms into a temporary shape at a material transition temperature;

[0072] Under the first driving condition, the reticular structure returns to the first initial shape, causing the intestinal support to deform from a temporary shape to an intermediate shape;

[0073] The negative Poisson's ratio structure returns to the second initial shape under the second driving condition, causing the intestinal scaffold to deform from the intermediate shape to the initial shape; wherein the first driving condition is different from the second driving condition.

[0074] In this invention, under the first driving condition, only the mesh structure deforms, while the negative Poisson's ratio structure remains unchanged, and the intestinal stent deforms from a temporary shape to an intermediate shape. Under the second driving condition, the mesh structure no longer deforms, but the negative Poisson's ratio structure deforms, and the intestinal stent deforms from the intermediate shape back to its initial shape. It should be noted that the first initial shape represents the initial shape of the mesh structure when it recovers from the reduced temporary shape to its original shape; the second initial shape represents the initial shape of the negative Poisson's ratio structure when it recovers from the reduced temporary shape to its original shape.

[0075] According to some preferred embodiments, the hydrogel is at least one of chitosan, cellulose, hyaluronic acid, heparin, alginate, polyacrylic acid, polyethylene glycol, polymethacrylic acid, polyvinyl alcohol, polyacrylamide or poly(N-isopropylacrylamide) with stress-responsive properties.

[0076] The drug-loaded layer responds to external stimuli to control the drug release rate; external stimuli include one or more of pH, light, magnetism, temperature, specific ions, or enzymes.

[0077] In this invention, the erosion and degradation of the drug-loaded hydrogel by human bodily fluids leads to the slow release and dissolution of the drug. The degradation rate of the drug-loaded layer is generally determined by its composition, and standard PK animal tests can be used to select one or more polymers to confirm that the polymer has completed degradation 45 to 90 days after implantation.

[0078] According to some preferred embodiments, the mass ratio of the drug to the hydrogel is 1:(10-20) (for example, it can be 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19 or 1:20).

[0079] In this invention, experiments have shown that if the mass ratio of drug to hydrogel is higher than 1:10, the amount of hydrogel used is too small, the stress response performance of the drug-carrying layer is poor, which will affect the drug release rate and the convenience of drug delivery; if the mass ratio of drug to hydrogel is lower than 1:20, the amount of drug used is too small, the amount of drug-carrying layer is too small, and the therapeutic effect is reduced.

[0080] Specifically, the medication selected includes one or more of the following: anti-tumor drugs, anti-infective drugs, antiviral drugs, antifungal drugs, anti-inflammatory analgesics, and immune enhancers. After intestinal stent implantation, friction with the patient's surgical site and scars can cause discomfort, even skin damage or infection. Intestinal stents containing anti-cancer drugs, anti-infective drugs, anti-inflammatory analgesics, and immune enhancers release these drugs into the patient's affected intestine, achieving therapeutic effects such as inhibiting cancer cell growth and spread, preventing or treating wound infections, providing anti-inflammatory and analgesic effects, or enhancing immunity.

[0081] More specifically, the antitumor drugs are one or more of oxaliplatin, acrylamide, paclitaxel, docetaxel, gemcitabine, capecitabine, rituximab, hydroxycamptothecin, pirarubicin, or epirubicin; the anti-infective drugs are one or more of β-lactam antibiotics, aminoglycoside antibiotics, macrolide antibiotics, or quinolones; the antiviral drugs are one or more of ribavirin, acyclovir, or ganciclovir; and the anti-inflammatory and analgesic drugs are aspirin, acetaminophen, etc. One or more of the following: phenol, indomethacin, naproxen, naproxen, diclofenac, ibuprofen, nimesulide, rofecoxib, or celecoxib; antifungal drugs such as clotrimazole or ketoconazole; and immune enhancers such as chemically synthesized drugs (e.g., levamisole, isoprotocin), human or animal immune products (e.g., thymosin, transfer factor, interferon, interleukin), drugs of microbial origin (e.g., BCG), fungal polysaccharides (e.g., lentinan), or effective components of traditional Chinese medicine.

[0082] The present invention also provides a method for preparing the above-mentioned anti-restenosis shape memory polymer intestinal scaffold, the method comprising:

[0083] (1) Design a three-dimensional structural model of an intestinal scaffold including a tubular scaffold and a drug-loaded layer;

[0084] (2) Determine the shape memory material used for the tubular scaffold and drug-loaded layer, and use 4D printing technology to print multiple materials. After molding, obtain a 4D printed intestinal scaffold with the initial shape.

[0085] In this invention, 4D printing technology includes, but is not limited to, fused deposition modeling (FDM), direct-write molding, stereolithography, or polymer jetting. The method for fabricating an anti-restenosis shape memory polymer intestinal stent provided by this invention utilizes 4D printing technology to prepare the intestinal stent. This method is not limited by complex structures, is suitable for personalized customization of intestinal stents, and has broad application prospects. Furthermore, it features rapid prototyping, significantly shortening the preparation time of the intestinal stent mold. The fabrication cost is low, the method is simple, and it is highly practical, easily accepted by consumers, and has significant social and economic benefits.

[0086] According to some preferred embodiments, the drug-loaded layer consists of a drug and a hydrogel with stress-responsive properties, wherein the mass ratio of the drug to the hydrogel is 1:(10-20).

[0087] According to some preferred embodiments, the tubular support includes a mesh structure and a negative Poisson's ratio structure; the driving conditions of the mesh structure and the negative Poisson's ratio structure are different, and the negative Poisson's ratio structure is located at the node of the mesh structure.

[0088] In this invention, in practical application, the anti-restenosis shape memory polymer intestinal 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 intestinal stent is restored to its initial shape by a first driving condition (e.g., water at around 37°C), which supports the intestine. At this time, the intestinal stent is in an intermediate shape. When restenosis occurs in the intestinal lesion, the negative Poisson's ratio structure of the intestinal stent is restored to its initial shape by a second driving condition (e.g., driven by a magnetic field or light). At this time, the intestinal stent is deformed from the intermediate shape to the initial shape, which further enhances the support effect of the intestinal stent and plays a role in resisting intestinal restenosis.

[0089] It should be noted that the initial and intermediate shapes of the anti-restenosis shape memory polymer intestinal stent are designed and established by preoperatively collecting medical imaging data of the patient's tumor, intestinal fistula or incision and surrounding tissues using human 3D scanner, magnetic resonance imaging (MRI) technology, CT scan technology, etc., and then processing the obtained data using medical simulation software, computer-aided design software, etc., so that the intestinal stent that returns to the initial shape can provide better support for the patient's intestine and drug delivery function.

[0090] In this invention, since the driving conditions of the mesh structure and the negative Poisson's ratio structure are relatively independent, the intestinal stent can perform its function of supporting the intestine while the negative Poisson's ratio structure of the intestinal stent can be driven according to the patient's actual situation to treat the patient's intestinal restenosis. Combined with a drug-loaded hydrogel epidermis that can control the drug release rate, it is beneficial to carry out personalized treatment for different patients, thereby reducing the patient's pain.

[0091] To more clearly illustrate the technical solution and advantages of the present invention, the following describes in detail a shape memory polymer intestinal stent for resisting restenosis and its preparation method through several embodiments.

[0092] Example 1

[0093] Methods for preparing anti-restenosis shape memory polymer intestinal scaffolds include:

[0094] S1. Diagnose the size and shape of the intestinal obstruction or fistula site, and design a three-dimensional structural model of the tubular stent, such as... Figure 1 and Figure 2 As shown; wherein, the tubular scaffold includes a mesh structure 1 and a negative Poisson's ratio structure 2, and the negative Poisson's ratio structure 2 is located at the node of the mesh structure 1, and the drug-loaded layer 3 is embedded in the mesh structure 1;

[0095] S2. Determine the materials with a network structure and negative Poisson's ratio structure (where the mass ratio of shape memory polymer to functional filler is 3:1); the drug-loaded layer consists of a drug and a hydrogel with stress-responsive properties, wherein the mass ratio of drug to hydrogel is 1:10.

[0096] The model designed in step S1 is printed using multi-material methods such as fused deposition modeling or direct write printing. After molding, a 4D-printed tubular scaffold with an embedded drug-loaded layer is obtained, which is an intestinal scaffold with an initial shape.

[0097] Application of intestinal stents: Intestinal stents are shaped into a temporary shape at the glass transition temperature. After implantation, the mesh structure of the intestinal stent returns to its initial shape through the driving action of water, providing support for the patient's intestine. At this time, the intestinal stent is in an intermediate shape. When intestinal restenosis occurs during the postoperative recovery process, the negative Poisson's ratio structure of the intestinal stent also returns to its initial shape through the driving action of magnetic field or light. At this time, the intestinal stent is in its initial shape, playing a role in preventing intestinal restenosis.

[0098] Specifically, regarding the application of intestinal stents, such as Figures 3 to 6 As shown, after obtaining as Figure 5 After shaping the intestinal scaffold as shown, the intestinal scaffold is heated to its glass transition temperature and shaped. An external force is applied and held for 5-10 seconds until the intestinal scaffold cools to room temperature. The intestinal scaffold is then endowed with the following properties: Figure 3 The temporary shape shown is that of an intestinal stent. The temporary shape of the intestinal stent can be designed to be small and easily implanted minimally invasively. After implantation, it deforms and returns to its preset three-dimensional shape, making minimally invasive surgical implantation of intestinal stents possible. The restenosis-resistant shape memory polymer intestinal stent deforms at the material transition temperature as shown... Figure 3 The temporary shape shown, after being compressed and cooled to room temperature, is implanted in the human body or placed in an environment simulating human body fluids. Driven by water, the mesh structure of the intestinal stent can return to its initial shape at around 37°C, thus supporting the intestine. At this time, the intestinal stent appears as follows: Figure 4 The intermediate shape shown. When intestinal restenosis occurs during the postoperative recovery process, the negative Poisson's ratio structure in the intestinal stent can be restored to its initial shape at around 45°C through the driving effect of a magnetic field or light. At this time, the intestinal stent presents as shown in the figure. Figure 5 The initial shape shown further enhances the support effect of the intestinal stent, thereby playing a role in preventing intestinal restenosis and ensuring that the intestinal stent can still exert a good therapeutic effect even when faced with intestinal restenosis in patients. Figure 6 From left to right: the temporary shape, intermediate shape, and initial shape of the intestinal stent. Figure 6 The changes in the shape of the intestinal scaffold after recovery are shown.

[0099] Example 2

[0100] Methods for preparing anti-restenosis shape memory polymer intestinal scaffolds include:

[0101] S1. Diagnose the size and shape of the intestinal obstruction or fistula site, and design a three-dimensional structural model of the tubular stent; wherein, the tubular stent includes a mesh structure and a negative Poisson's ratio structure, and the negative Poisson's ratio structure is located at the node of the mesh structure, and the drug-loaded layer is embedded in the mesh structure;

[0102] S2. Determine the materials with network structure and negative Poisson's ratio structure (where the mass ratio of shape memory polymer to functional filler is 4:1); the drug-loaded layer consists of a drug and a hydrogel with stress-responsive properties, where the mass ratio of drug to hydrogel is 1:10.

[0103] The model designed in step S1 is printed using multi-material methods such as fused deposition modeling or direct write printing. After molding, a 4D-printed tubular scaffold with an embedded drug-loaded layer is obtained, which is an intestinal scaffold with an initial shape.

[0104] Application of intestinal stents: Intestinal stents are shaped into a temporary shape at the glass transition temperature. After implantation, the mesh structure of the intestinal stent returns to its initial shape through the driving action of water, providing support for the patient's intestine. At this time, the intestinal stent is in an intermediate shape. When intestinal restenosis occurs during the postoperative recovery process, the negative Poisson's ratio structure of the intestinal stent also returns to its initial shape through the driving action of magnetic field or light. At this time, the intestinal stent is in its initial shape, playing a role in preventing intestinal restenosis.

[0105] Example 3

[0106] Methods for preparing anti-restenosis shape memory polymer intestinal scaffolds include:

[0107] S1. Diagnose the size and shape of the intestinal obstruction or fistula site, and design a three-dimensional structural model of the tubular stent; wherein, the tubular stent includes a mesh structure and a negative Poisson's ratio structure, and the negative Poisson's ratio structure is located at the node of the mesh structure, and the drug-loaded layer is embedded in the mesh structure;

[0108] S2. Determine the materials for the network structure and negative Poisson's ratio structure (wherein, the mass ratio of shape memory polymer to functional filler is 5:1); the drug-loaded layer consists of a drug and a hydrogel with stress-responsive properties, wherein the mass ratio of drug to hydrogel is 1:10.

[0109] The model designed in step S1 is printed using multi-material methods such as fused deposition modeling or direct write printing. After molding, a 4D-printed tubular scaffold with an embedded drug-loaded layer is obtained, which is an intestinal scaffold with an initial shape.

[0110] Application of intestinal stents: Intestinal stents are shaped into a temporary shape at the glass transition temperature. After implantation, the mesh structure of the intestinal stent returns to its initial shape through the driving action of water, providing support for the patient's intestine. At this time, the intestinal stent is in an intermediate shape. When intestinal restenosis occurs during the postoperative recovery process, the negative Poisson's ratio structure of the intestinal stent also returns to its initial shape through the driving action of magnetic field or light. At this time, the intestinal stent is in its initial shape, playing a role in preventing intestinal restenosis.

[0111] Example 4

[0112] Methods for preparing anti-restenosis shape memory polymer intestinal scaffolds include:

[0113] S1. Diagnose the size and shape of the intestinal obstruction or fistula site, and design a three-dimensional structural model of the tubular stent; wherein, the tubular stent includes a mesh structure and a negative Poisson's ratio structure, and the negative Poisson's ratio structure is located at the node of the mesh structure, and the drug-loaded layer is embedded in the mesh structure;

[0114] S2. Determine the materials with a network structure and negative Poisson's ratio structure (where the mass ratio of shape memory polymer to functional filler is 5:1); the drug-loaded layer consists of a drug and a hydrogel with stress-responsive properties, wherein the mass ratio of drug to hydrogel is 1:15;

[0115] The model designed in step S1 is printed using multi-material methods such as fused deposition modeling or direct write printing. After molding, a 4D-printed tubular scaffold with an embedded drug-loaded layer is obtained, which is an intestinal scaffold with an initial shape.

[0116] Application of intestinal stents: Intestinal stents are shaped into a temporary shape at the glass transition temperature. After implantation, the mesh structure of the intestinal stent returns to its initial shape through the driving action of water, providing support for the patient's intestine. At this time, the intestinal stent is in an intermediate shape. When intestinal restenosis occurs during the postoperative recovery process, the negative Poisson's ratio structure of the intestinal stent also returns to its initial shape through the driving action of magnetic field or light. At this time, the intestinal stent is in its initial shape, playing a role in preventing intestinal restenosis.

[0117] Example 5

[0118] Methods for preparing anti-restenosis shape memory polymer intestinal scaffolds include:

[0119] S1. Diagnose the size and shape of the intestinal obstruction or fistula site, and design a three-dimensional structural model of the tubular stent; wherein, the tubular stent includes a mesh structure and a negative Poisson's ratio structure, and the negative Poisson's ratio structure is located at the node of the mesh structure, and the drug-loaded layer is embedded in the mesh structure;

[0120] S2. Determine the materials with a network structure and a negative Poisson's ratio structure (where the mass ratio of shape memory polymer to functional filler is 5:1); the drug-loaded layer consists of a drug and a hydrogel with stress-responsive properties, where the mass ratio of drug to hydrogel is 1:20.

[0121] The model designed in step S1 is printed using multi-material methods such as fused deposition modeling or direct write printing. After molding, a 4D-printed tubular scaffold with an embedded drug-loaded layer is obtained, which is an intestinal scaffold with an initial shape.

[0122] Application of intestinal stents: Intestinal stents are shaped into a temporary shape at the glass transition temperature. After implantation, the mesh structure of the intestinal stent returns to its initial shape through the driving action of water, providing support for the patient's intestine. At this time, the intestinal stent is in an intermediate shape. When intestinal restenosis occurs during the postoperative recovery process, the negative Poisson's ratio structure of the intestinal stent also returns to its initial shape through the driving action of magnetic field or light. At this time, the intestinal stent is in its initial shape, playing a role in preventing intestinal restenosis.

[0123] 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. An anti-restenotic shape memory polymer enteric stent, characterized in that, The intestinal stent includes a tubular stent and a drug-loaded layer embedded in the tubular stent; Both the tubular scaffold and the drug-loaded layer are biodegradable materials; the tubular scaffold is composed of at least two shape memory materials with different driving conditions; the drug-loaded layer is composed of drugs and hydrogels. The tubular support includes a mesh structure and a negative Poisson's ratio structure; the driving conditions of the mesh structure and the negative Poisson's ratio structure are different, and the negative Poisson's ratio structure is located at the node of the mesh structure; the shape memory material used in the mesh structure includes at least one of polyurethane, polyester, polyvinyl alcohol, or polyethylene glycol; the negative Poisson's ratio structure is composed of a shape memory polymer and a functional filler; the functional filler is a magnetic filler or a photothermal filler; the shape memory polymer is at least one of polycaprolactone, polylactic acid, polyurethane, poly(ethylene glycol) diacrylate, acrylic epoxidized soybean oil, or poly(d,l-lactide-co-trimethylene carbonate); The intestinal scaffold includes an initial shape, an intermediate shape, and a temporary shape; the volume of the initial shape is larger than the volumes of the intermediate shape and the temporary shape; the volume of the intermediate shape is larger than the volume of the temporary shape; wherein, the intestinal scaffold deforms into different shapes under different driving conditions; The intestinal scaffold deforms into the temporary shape at the material transition temperature; The mesh structure recovers to the first initial shape under the first driving condition, causing the intestinal scaffold to deform from the temporary shape to the intermediate shape; The negative Poisson's ratio structure recovers to the second initial shape under the second driving condition, causing the intestinal scaffold to deform from the intermediate shape to the initial shape.

2. The anti-restenosis shape memory polymer intestinal stent according to claim 1, characterized in that, The mass ratio of the shape memory polymer to the functional filler in the negative Poisson's ratio structure is (3~5):

1.

3. The anti-restenotic shape memory polymer enteric stent of claim 1, wherein, The magnetic filler is at least one of γ-ferric oxide, iron tetroxide, neodymium iron boron, carbonyl iron, and nickel-zinc ferrite.

4. The anti-restenotic shape memory polymer enteric stent of claim 1, wherein, The photothermal filler is at least one of gold nanoparticles, carbon black, graphene oxide, or black phosphorus.

5. The anti-restenosis shape memory polymer intestinal stent according to any one of claims 1 to 4, characterized in that, The hydrogel is at least one of the following: chitosan, cellulose, hyaluronic acid, heparin, alginate, polyacrylic acid, polyethylene glycol, polymethacrylic acid, polyvinyl alcohol, polyacrylamide, or poly(N-isopropylacrylamide) with stress-responsive properties. The drug-loaded layer responds to external stimuli to control the drug release rate; the external stimuli include one or more of pH, light, magnetism, temperature, specific ions, or enzymes.

6. The anti-restenosis shape memory polymer intestinal stent according to any one of claims 1 to 4, characterized in that, The mass ratio of the drug to the hydrogel is 1:(10~20).

7. A method of producing the anti-restenotic shape memory polymer enterosolical stent according to any one of claims 1 to 6, characterized by, The preparation method includes: (1) Design a three-dimensional structural model of an intestinal scaffold including a tubular scaffold and a drug-loaded layer; (2) Determine the shape memory material used for the tubular stent and the drug-loaded layer, and use 4D printing technology to perform multi-material printing to obtain a 4D printed intestinal stent with an initial shape after molding.

8. The preparation method according to claim 7, characterized in that, The drug-loaded layer consists of a drug and a hydrogel with stress-responsive properties, wherein the mass ratio of the drug to the hydrogel is 1:(10~20).

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