Multi-stage bionic 3D printing cross-scale composite lumen stent, preparation method and application of multi-stage bionic 3D printing cross-scale composite lumen stent

Abstract

The invention relates to the technical field of 3D printing, in particular to a multi-stage bionic 3D printing cross-scale composite lumen stent, a preparation method and application of the multi-stage bionic 3D printing cross-scale composite lumen stent. A hierarchical regulation and control degradation strategy is adopted, the overall structure simulates a real lumen tissue structure, the physical performance is met for the full life cycle, an inner-middle-outer composite lumen stent is established, the inner layer is an ordered fiber layer, the middle layer is a net-shaped supporting layer, the outer layer is a disordered fiber layer, and the fiber layers achieve rapid controllable degradation after soft tissue reconstruction. Reconstruction of the intima is prevented from being hindered, a safer, more effective and more personalized solution is provided for treatment of various lumen diseases, and therefore the treatment effect and life quality of a patient are remarkably improved.

Description

Technical Field

[0001] The present application relates to the field of 3D printing technology, and specifically to a multi-level bionic 3D printed cross-scale composite luminal stent, a preparation method and its application. Background Art

[0002] As a medical device that provides effective support, luminal biostents are widely used in tissue reconstruction, including those for blood vessels, trachea, and esophagus. They maintain or reconstruct the integrity of the human cavity structure through mechanical support, playing a key role in interventional therapy.

[0003] Tissue repair is a dynamic process, but the luminal stents in current research only meet a single supporting role, resulting in poor compatibility with human tissues. Secondly, the use of a single material makes it difficult for the stent to take into account both rigidity and flexibility, which may cause the stent to break or damage the surrounding tissues. After the stent is implanted, problems such as inflammation, intimal hyperplasia, and matrix deposition will occur one after another, which cannot match the reconstruction of the luminal tissue, leading to restenosis and secondary intervention. To meet these challenges, the bionic multi-layer stent can simulate the multi-layer structure of natural luminal tissue, which can not only meet the basic support function, but also achieve the coordinated optimization of multiple performances. First, the multi-layer structure design can better simulate the mechanical properties of natural tissue and improve the biomechanical compatibility of the stent; different materials can be used at different layers to achieve a perfect combination of rigid support and flexible transition, reducing stimulation to surrounding tissues.

[0004] In recent years, the rapid development of 3D printing technology has provided new possibilities for solving the above problems. 3D printing technology has significant advantages such as high design freedom, the realization of complex structures, and a wide range of material selection, which has opened up new avenues for the innovative design and manufacture of composite stents. However, how to make full use of 3D printing technology to manufacture composite luminal stents with multi-level bionic structures, cross-scale designs, excellent mechanical properties and biocompatibility is still a technical problem that needs to be solved urgently. In particular, how to achieve the precise ratio and distribution of multiple materials in the 3D printing process, how to ensure good combination of different materials, and how to achieve coordinated optimization of the performance of various parts of the composite stent through structural design are all major challenges facing current research.

[0005] The development of multi-level bionic 3D printed cross-scale composite luminal stents and their preparation methods are of great significance for improving the comprehensive performance and clinical application effects of the stents.

[0006] The information in this background technology section is only intended to enhance understanding of the overall background of the application and is not necessarily regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art. Summary of the Invention

[0007] In order to solve the above problems, this application provides a multi-level bionic 3D printed cross-scale composite luminal stent and its preparation method, which is optimized in terms of structural design, material selection, mechanical properties, biocompatibility and functionality, providing a safer, more effective and personalized solution for the treatment of various luminal diseases, thereby significantly improving the treatment effect and quality of life of patients.

[0008] In some embodiments of the present application, a method for preparing a multi-level biomimetic 3D-printed cross-scale composite luminal stent is provided, comprising the following steps:

[0009] (1) Scan digital images of blood vessels to construct a three-dimensional anatomical structure model of the luminal stent. Perform a comprehensive numerical analysis of the stent flow field changes, liquid spreadability, and stent mechanical effects. Use the model to optimize the stent blend material ratio, tube diameter, wire diameter, and base structure to determine the structural parameters.

[0010] (2) preheating the first degradable polymer material at a predetermined temperature for a predetermined time for melt spraying;

[0011] (3) Applying airflow field to drive melt spinning technology, the degradable polymer material is jet-spinned on the substrate. By changing the placement of the substrate and the printing height, ordered inner-layer spun fibers with different orientations and porosities are obtained. As the inner layer of the vascular stent, the fiber diameter is controlled between 5-20 μm, the porosity is controlled between 37%-53%, and the thickness is controlled within 50 μm;

[0012] (4) Weighing a second degradable polymer material, dissolving it in an organic solvent, pouring it into a container and allowing it to stand until the solvent evaporates, thereby obtaining a mixed second degradable polymer material;

[0013] (5) The mixed material in step (4) is used to print a mesh support structure of a middle support layer on a substrate having an inner layer of spun fibers by electric field direct writing technology; support layers with different wire diameters are obtained by adjusting the printing air pressure and the printing voltage to meet the support performance requirements of different lesion locations; the printing wire diameter range is 20-180 μm, the printing gap range is between 60 μm-2000 μm, the thickness is controlled within 100 μm, and the nozzle printing temperature is adjusted to ensure a tight connection between the inner layer of spun fibers and the middle support layer;

[0014] (6) using a third degradable polymer material and using an airflow field driven melt-blowing technology to perform outer layer spinning on the substrate of the inner-middle layer printed in step (5), thereby printing a vascular stent having an inner-middle-outer layer; the diameter of the spun fiber is controlled to be between 0.5-5 μm, and the thickness is controlled to be within 5 μm;

[0015] (7) Soaking the substrate with the vascular stent in step (6) in an ultrapure ice-water mixture, and after the stent is separated from the substrate, drying the stent to obtain an inner-middle-outer three-layer luminal stent with a multifunctional layer.

[0016] In some embodiments of the present application, the first degradable polymer material is polylactic acid (PLA) or poly (L-lactic acid) (PLLA), the second degradable polymer material is polycaprolactone (PCL) / polylactic acid (PLA) copolymer, and the third degradable polymer material is poly (L-lactic acid) (PLLA).

[0017] In some embodiments of the present application, after the outer layer of spinning is prepared in step (6), nerve growth factor (NGF) and / or brain-derived neurotrophic factor (BDNF) are dissolved in phosphate buffered saline (PBS), and the biological factor solution is evenly loaded onto the outer layer of spinning by spraying.

[0018] In some embodiments of the present application, digital images of blood vessels are obtained by CT and MRI scans of the patient.

[0019] In some embodiments of the present application, in step (2), the preset temperature is 220-280° C., and the preset time is 1-2 hours.

[0020] In some embodiments of the present application, the organic solvent in step (4) is dichloromethane (DCM).

[0021] In some embodiments of the present application, step (4) specifically comprises weighing polycaprolactone (PCL) particles and polylactic acid (PLA) powder, placing the dried two materials into a beaker containing dichloromethane (DCM), stirring the solution with a magnetic stirrer at room temperature for 6 hours, pouring the mixed solution into a glass petri dish, and allowing it to stand at 40°C for 4 hours to allow the solvent to completely evaporate and the blended material to become a solid. The material after the solvent evaporates is cut into strips for later use.

[0022] In some embodiments of the present application, the substrate is selected within a range of 3 mm to 10 cm based on the diameter of the blood vessels at the lesion site.

[0023] In some embodiments of the present application, in step (3), a high-speed airflow field is used to drive 3D direct writing technology to continuously form a fiber functional layer, thereby avoiding the residue of toxic solvents and designing different porosities to meet the needs of different cell cultures.

[0024] In some embodiments of the present application, in step (4), the support strength and support time are optimized by adjusting the ratio of polycaprolactone (PCL) and polylactic acid (PLA) according to the support requirements of the lesion site; the ratio of PCL:PLA ranges from 1:1 to 1:10, which can meet the support requirements of different lesion sites.

[0025] In some embodiments of the present application, step (5) uses electric field driven 3D printing technology to construct a stent support layer on the ordered fibers, and the support and compliance of the tubular stent are met through the support units and the connecting units.

[0026] In some embodiments of the present application, step (6) utilizes a high-speed airflow field to drive microfiber 3D direct writing technology, controls the internal and external air pressures in the high-speed airflow field to construct a fine and orderly micron-level protective layer, satisfies the interaction of cell nutrients, and reduces stress concentration on the tube wall, thereby achieving high-fidelity conversion from personalized design models to real objects.

[0027] In some embodiments of the present application, in steps (3) and (6), the device used for the airflow field driven meltblown spinning technology includes:

[0028] Motion module, molten material printing nozzle module, molten material feeding module, temperature control module, high-speed airflow control module, rotary axis workbench and frame.

[0029] In some embodiments of the present application, the motion module includes an X-axis, dual Y-axes, and a Z-axis, wherein the dual Y-axes are mounted on a frame, the X-axis is vertically mounted on the dual Y-axes to form a gantry structure, and the Z-axis is mounted on the X-axis and remains perpendicular to the horizontal plane.

[0030] In some embodiments of the present application, the molten material printing nozzle module mainly includes a barrel, an adapter, and a printing nozzle. The adapter is equipped with a sealing ring, assembled with the barrel, and assembled on the Z-axis of the motion module. The printing nozzle is connected to the barrel.

[0031] In some embodiments of the present application, the molten material feeding module is composed of a first air pressure valve, a first air pressure pump, a first pressure gauge, and a three-way joint. The first air pressure pump is used to provide air pressure and adjust the air pressure display value to adjust the discharge speed. The three-way joint is connected to the first pressure gauge, the molten material printing nozzle module, and the high-speed airflow control module through a hose.

[0032] In some embodiments of the present application, the temperature control module includes a first heating element, a second heating element and a temperature control system thereof, wherein the first heating element can be a heating ring, which is used to control the temperature of the molten material in the barrel; the second heating element is used to heat the temperature of the material at the printing nozzle, so as to prevent the material at the printing nozzle from cooling and solidifying and clogging the nozzle, so as to better control the state of the material.

[0033] In some embodiments of the present application, the temperature control module further includes a heating base plate for heating the substrate placed thereon. Adjusting the heating base plate to a suitable temperature can prevent the obtained fiber structure from warping due to deformation caused by internal stress.

[0034] In some embodiments of the present application, the high-speed airflow control module mainly includes a second air pressure valve, a second air pressure pump, a second air pressure gauge and a hollow copper tube. In order to match the size of the print nozzle, the hollow copper tube is selected with a diameter smaller than the nozzle diameter. The hollow copper tube passes through the three-way joint, the adapter, the barrel and all the way to the print nozzle. The second air pressure gauge is used to control the flow rate of the high-speed airflow entering the hollow copper tube.

[0035] In some embodiments of the present application, the rotary workbench mainly includes a base plate, a bearing, two oppositely arranged fixed brackets, a motor, a chuck and a pin. The two oppositely arranged fixed brackets are installed on the base plate, and the motor is installed at the same time. The chucks at both ends are respectively installed on the fixed brackets at both ends through bearings. The chuck is installed on one side and cooperates with the motor through a coupling. The chuck is installed on the other side to align and fix the tubular printing substrate.

[0036] In some embodiments of the present application, the second heating element may be a heating block, and the second heating element cooperates with the fixing screw to control the coaxiality of the hollow copper tube and the nozzle.

[0037] For example, holes are drilled on the outside of the second heating element and at appropriate positions of the print head, and the dimensions are calculated so that the fixing screws fit the threaded holes of the second heating element and the print head and support the hollow copper tube inside the print head, controlling the hollow copper tube to be coaxial with the print head for better spraying effect.

[0038] In some embodiments of the present application, when the above-mentioned device is used to perform printing in steps (3) and (6), the following steps are included:

[0039] (1) The first degradable polymer material / the third degradable polymer material is loaded into a barrel, and the temperatures of the first heating element and the second heating element are set according to the material properties to ensure that the material in the barrel will not be degraded due to excessive temperature, while ensuring the viscosity of the material so that the melted material can flow out smoothly;

[0040] (2) Fix the rotary axis platform to the XY axis base plate of the motion module, install the chuck on the fixed bracket, adjust the coaxiality of the ejector pin and the chuck, and use the chuck and ejector pin to fix the tubular printing substrate, i.e., the receiving substrate;

[0041] (3) Open the motion module, use the motion module to adjust the position of the print head, open the rotating shaft, first open the first air pressure valve, adjust the first air pressure gauge to control the flow rate of the molten material, then open the second air pressure valve and the second air pressure gauge to control the air flow rate in the hollow copper tube, and print according to the preset path;

[0042] (4) After printing is completed, the rotating shaft, the first and second air pressure valves, and the first and second heating elements are closed, and the print head is moved to the device origin.

[0043] In some embodiments of the present application, the biomimetic cross-scale multi-level gradient composite scaffold realizes a fully degradable dynamic regulation function through the construction and evaluation and regulation of the bioactive gradient functionalized surface in tissue repair.

[0044] In some other embodiments of the present application, a multi-level bionic 3D printed multi-level bionic cross-scale composite luminal stent is also provided, which is prepared by one of the above-mentioned preparation methods.

[0045] In some embodiments of the present application, the luminal stent includes a thin-walled three-layer tubular mesh stent, the bottom layer of the stent is an ordered fiber layer, which simulates the ordered cells of endothelial cells and is conducive to the circulation of body fluids; the middle layer of the luminal stent imitates the crossed and branched smooth muscle cells, and a mesh support structure is selected to provide core support function to ensure the overall structural stability of the stent; the outer layer of the luminal stent imitates loose connective tissue and selects disordered microfibers to reduce stress concentration on the tube wall tissue.

[0046] In some further embodiments of the present application, the above-mentioned luminal stent is also provided as a support device for use on body luminal tissues, wherein the luminal tissues are nerve conduits, vascular stents, esophageal stents, tracheal stents, urethral stents, bile duct stents and bone tissue engineering scaffolds.

[0047] In some embodiments of the present application, the luminal stent serves as a vascular stent to support a narrowed and occluded segment of a blood vessel, thereby reducing elastic retraction and reshaping of the blood vessel and maintaining smooth blood flow in the luminal cavity.

[0048] In some embodiments of the present application, the luminal stent is used as a tracheal stent, a bile duct stent, and an esophageal stent as an important palliative treatment for lung cancer, bile duct cancer, and esophageal cancer to relieve obstruction, improve quality of life, and prolong survival.

[0049] Compared with the prior art, the present invention has the following beneficial effects:

[0050] 1. This invention uses 3D printing technology to achieve the integrated fabrication of complex, multi-layered gradient structures, which can better mimic the structural characteristics of natural tissue. This biomimetic design not only improves the biocompatibility of the scaffold but also promotes cell proliferation and differentiation, accelerating the tissue repair process.

[0051] 2. This invention achieves comprehensive optimization from microscopic fibers to macroscopic scaffolds. At the microscale, cell compatibility is enhanced by manipulating the material's molecular structure and surface morphology. At the macroscale, long-term, stable support is ensured by optimizing the scaffold's overall structure and mechanical properties. This cross-scale design approach significantly improves the scaffold's overall performance.

[0052] 3. This invention utilizes a hierarchical degradation strategy, with the overall structure mimicking the actual luminal tissue structure, ensuring consistent physical performance throughout the entire lifecycle. The scaffold's degradation dynamics precisely match the surrounding tissue reconstruction. After soft tissue reconstruction, the fibrous layer undergoes rapid and controlled degradation, avoiding obstruction of intimal reconstruction. Following remodeling of the luminal bioremodeling, the support layer undergoes controlled degradation, ensuring synchronized coordination between the mechanical environment and tissue remodeling, achieving controlled degradation from local to global scale.

[0053] 4. This invention achieves active regulation of cell behavior and tissue reconstruction through the design of a bioactive gradient functionalized surface. This functionalized surface can be loaded with various biological factors, such as growth factors and anti-inflammatory factors, thereby promoting tissue healing, inhibiting inflammatory responses, and enhancing the therapeutic efficacy of the stent.

[0054] 5. This invention studies the mechanism of multi-material interface bonding to achieve coordinated control of microstructure and macromorphology. A multi-morphological support layer is prepared using electric-field-driven 3D printing technology. By regulating the PCL / PLA material ratio and printing wire diameter, the conformability and mechanical support of complex luminal structures are unified. High-speed airflow-driven 3D direct writing technology is used to prepare a high-speed, continuous fiber functional layer, avoiding the presence of toxic solvent residues. Different porosities are designed to accommodate diverse cell culture needs.

[0055] 6. This application uses an external material and internal air printing device to directly heat the material and also has a certain heating effect on the copper tube. It has the advantages of not wasting a lot of energy to heat the air externally, saving energy, etc.

[0056] 7. This application can print a macro-controllable and micro-adjustable spinning structure through a high-precision XYZ three-axis motion platform.

[0057] 8. Use dual heating elements to control the temperature. The heating temperature of the first heating element on the barrel is slightly lower than the heating temperature of the second heating element on the print nozzle. When the first heating element is heated stably, adjust the second heating element to make the nozzle temperature slightly higher than the barrel temperature, and increase it in a gradient. The material can be gradually heated in the barrel and nozzle in a gradient increasing manner until the required printing temperature is finally reached. This is conducive to better control of the temperature of the printing material at the nozzle, and then stabilize the viscosity changes of the printing material caused by heating temperature fluctuations. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0059] Figure 1 Schematic diagram of a multi-level bionic 3D printed cross-scale composite luminal stent in some embodiments of the present application;

[0060] Figure 2 Scanning electron microscope images of spinning structures with different porosities prepared by the method for preparing a multi-stage bionic 3D-printed cross-scale composite luminal stent in some embodiments of the present application;

[0061] Figure 3 This is a physical picture of the middle mesh support layer and the outer layer of disordered fibers added to the multi-level bionic 3D printed cross-scale composite luminal stent in some embodiments of the present application;

[0062] Figure 4 A physical image of a multi-level bionic 3D printed cross-scale composite luminal stent and a multi-layer vascular stent customized according to the strength requirements of different parts in some embodiments of the present application;

[0063] Figure 5 Schematic diagram of the device structure used in the airflow field driven meltblown spinning technology in some embodiments of the present application.

[0064] Figure 6 Schematic diagram of the disassembly and assembly of the coaxial nozzle of the molten material printing nozzle module in some embodiments of the present application;

[0065] Figure 7 It is a schematic structural diagram of the rotary axis workbench in some embodiments of the present application.

[0066] Among them, there are motion module 1, molten material printing nozzle module 2, molten material feeding module 3, temperature control module 4, high-speed airflow control module 5, rotary axis workbench 6, frame 7, X-axis 101, double Y-axis 102, Z-axis 103, barrel 201, adapter 202, printing nozzle 203, first pressure gauge 301, first heating element 401, second heating element 402, heating base plate 403, fixing screw 404, second pressure gauge 501, hollow copper tube 502, rotary workbench 6, base plate 601, bearing 602, fixed bracket 603, motor 604, chuck 605, and ejector pin 606. DETAILED DESCRIPTION

[0067] The following will be combined with the drawings in the embodiments of this application to clearly and completely describe the technical solutions in the embodiments of this application. Obviously, the embodiments described are only part of the embodiments of this application, not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of this application.

[0068] It should be noted that the following detailed description is illustrative and is intended to provide an explanation of the present invention in some embodiments of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0069] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof.

[0070] In the present application, terms such as "upper", "lower", "left", "right", "front", "back", "vertical", "horizontal", "side", "bottom", etc. indicating directions or positional relationships are based on the directions or positional relationships shown in the accompanying drawings. They are merely relational words determined for the convenience of describing the structural relationships of the various parts or elements of the present application, and do not specifically refer to any part or element in the present application, and should not be understood as limitations on the present application.

[0071] In this application, terms such as "fixed connection," "connected," and "connection" should be interpreted broadly to mean a fixed connection, an integral connection, or a detachable connection; a direct connection or an indirect connection through an intermediary. Relevant researchers or technicians in this field may determine the specific meaning of these terms in this application based on specific circumstances, and they should not be construed as limitations on this application.

[0072] In some embodiments of the present application, a method for preparing a multi-level biomimetic 3D-printed cross-scale composite luminal stent is provided, comprising the following steps:

[0073] (1) Scan digital images of blood vessels to construct a three-dimensional anatomical structure model of the luminal stent. Perform a comprehensive numerical analysis of the stent flow field changes, liquid spreadability, and stent mechanical effects. Use the model to optimize the stent blend material ratio, tube diameter, wire diameter, and base structure to determine the structural parameters.

[0074] (2) preheating the first degradable polymer material at a predetermined temperature for a predetermined time for melt spraying;

[0075] (3) Applying airflow field to drive melt spinning technology, the degradable polymer material is jet-spinned on the substrate. By changing the placement of the substrate and the printing height, ordered inner-layer spun fibers with different orientations and porosities are obtained. As the inner layer of the vascular stent, the fiber diameter is controlled between 5-20 μm, the porosity is controlled between 37%-53%, and the thickness is controlled within 50 μm;

[0076] (4) Weighing a second degradable polymer material, dissolving it in an organic solvent, pouring it into a container and allowing it to stand until the solvent evaporates, thereby obtaining a mixed second degradable polymer material;

[0077] (5) The mixed material in step (4) is used to print a mesh support structure of a middle support layer on a substrate having an inner layer of spun fibers by electric field direct writing technology; support layers with different wire diameters are obtained by adjusting the printing air pressure and the printing voltage to meet the support performance requirements of different lesion locations; the printing wire diameter range is 20-180 μm, the printing gap range is between 60 μm-2000 μm, the thickness is controlled within 100 μm, and the nozzle printing temperature is adjusted to ensure a tight connection between the inner layer of spun fibers and the middle support layer;

[0078] (6) using a third degradable polymer material and using an airflow field driven melt-blowing technology to perform outer layer spinning on the substrate of the inner-middle layer printed in step (5), thereby printing a vascular stent having an inner-middle-outer layer; the diameter of the spun fiber is controlled to be between 0.5-5 μm, and the thickness is controlled to be within 5 μm;

[0079] (7) Soaking the substrate with the vascular stent in step (6) in an ultrapure ice-water mixture, and after the stent is separated from the substrate, drying the stent to obtain an inner-middle-outer three-layer luminal stent with a multifunctional layer.

[0080] In some embodiments of the present application, the first degradable polymer material is polylactic acid (PLA) or poly (L-lactic acid) (PLLA), the second degradable polymer material is polycaprolactone (PCL) / polylactic acid (PLA) copolymer, and the third degradable polymer material is poly (L-lactic acid) (PLLA).

[0081] In some embodiments of the present application, after the outer layer of spinning is prepared in step (6), nerve growth factor (NGF) and / or brain-derived neurotrophic factor (BDNF) are dissolved in phosphate buffered saline (PBS), and the biological factor solution is evenly loaded onto the outer layer of spinning by spraying.

[0082] In some embodiments of the present application, digital images of blood vessels are obtained by CT and MRI scans of the patient.

[0083] In some embodiments of the present application, in step (2), the preset temperature is 220-280° C., and the preset time is 1-2 hours.

[0084] In some embodiments of the present application, the organic solvent in step (4) is dichloromethane (DCM).

[0085] In some embodiments of the present application, step (4) specifically comprises weighing polycaprolactone (PCL) particles and polylactic acid (PLA) powder, placing the dried two materials into a beaker containing dichloromethane (DCM), stirring the solution with a magnetic stirrer at room temperature for 6 hours, pouring the mixed solution into a glass petri dish, and allowing it to stand at 40°C for 4 hours to allow the solvent to completely evaporate and the blended material to become a solid. The material after the solvent evaporates is cut into strips for later use.

[0086] In some embodiments of the present application, the substrate is selected within a range of 3 mm to 10 cm based on the diameter of the blood vessels at the lesion site.

[0087] In some embodiments of the present application, in step (3), a high-speed airflow field is used to drive 3D direct writing technology to continuously form a fiber functional layer, thereby avoiding the residue of toxic solvents and designing different porosities to meet the needs of different cell cultures.

[0088] In some embodiments of the present application, in step (4), the support strength and support time are optimized by adjusting the ratio of polycaprolactone (PCL) and polylactic acid (PLA) according to the support requirements of the lesion site; the ratio of PCL:PLA ranges from 1:1 to 1:10, which can meet the support requirements of different lesion sites.

[0089] In some embodiments of the present application, step (5) uses electric field driven 3D printing technology to construct a stent support layer on the ordered fibers, and the support and compliance of the tubular stent are met through the support units and the connecting units.

[0090] In some embodiments of the present application, step (6) utilizes a high-speed airflow field to drive microfiber 3D direct writing technology, controls the internal and external air pressures in the high-speed airflow field to construct a fine and orderly micron-level protective layer, satisfies the interaction of cell nutrients, and reduces stress concentration on the tube wall, thereby achieving high-fidelity conversion from personalized design models to real objects.

[0091] In some embodiments of the present application, in steps (3) and (6), the device used for the airflow field driven meltblown spinning technology includes:

[0092] Motion module 1, molten material printing nozzle 203 module 2, molten material feeding module 3, temperature control module 4, high-speed airflow control module 5, rotating axis workbench 6, and frame 7.

[0093] In some embodiments of the present application, the motion module 1 includes an X-axis 101, dual Y-axes 102, and a Z-axis 103, wherein the dual Y-axes 102 are installed on the frame 7, the X-axis 101 is vertically installed on the dual Y-axes 102 to form a gantry structure, and the Z-axis 103 is installed on the X-axis 101 and remains perpendicular to the horizontal plane.

[0094] In some embodiments of the present application, the molten material printing nozzle 203 module 2 mainly includes a barrel 201, an adapter 202, and a printing nozzle 203. The adapter 202 is equipped with a sealing ring and is assembled with the barrel 201 and assembled on the Z-axis 103 of the motion module 1. The printing nozzle 203 is connected to the barrel 201.

[0095] In some embodiments of the present application, the molten material feeding module 3 is composed of a first air pressure valve, a first air pressure pump, a first air pressure gauge 301, and a three-way joint. The first air pressure pump is used to provide air pressure, adjust the air pressure indication value and thus adjust the discharge speed. The three-way joint is connected to the first air pressure gauge 301, the molten material printing nozzle 203 module 2, and the high-speed airflow control module 5 through a hose.

[0096] In some embodiments of the present application, the temperature control module 4 includes a first heating element 401, a second heating element 402 and a temperature control system thereof, wherein the first heating element 401 can be a heating ring for controlling the temperature of the molten material in the barrel 201; the second heating element 402 is used to heat the temperature of the material at the print nozzle 203, in order to prevent the material at the print nozzle 203 from cooling and solidifying and clogging the nozzle, so as to better control the state of the material.

[0097] In some embodiments of the present application, the temperature control module 4 further includes a heating base plate 403 for heating the substrate placed thereon. Adjusting the heating base plate 403 to a suitable temperature can prevent the obtained fiber structure from warping due to deformation caused by internal stress.

[0098] In some embodiments of the present application, the high-speed airflow control module 5 mainly includes a second air pressure valve, a second air pressure pump, a second air pressure gauge 501 and a hollow copper tube 502. In order to match the size of the print nozzle 203, the hollow copper tube 502 is selected to have a diameter smaller than the nozzle diameter. The hollow copper tube 502 passes through the three-way joint, the adapter 202, the barrel 201 and all the way to the print nozzle 203. The second air pressure gauge 501 is used to control the flow rate of the high-speed airflow entering the hollow copper tube 502.

[0099] In some embodiments of the present application, the rotary workbench 6 mainly includes a base plate 601, a bearing 602, two relatively arranged fixed brackets 603, a motor 604, a chuck 605 and a pin 606. The two relatively arranged fixed brackets 603 are installed on the base plate 601, and the motor 604 is installed at the same time. The chucks at both ends are respectively installed on the fixed brackets 603 at both ends through bearings 602. The chuck on one side is installed with the chuck and cooperates with the motor 604 through a coupling. The chuck on the other side is installed with the pin 606 to align and fix the tubular printing substrate.

[0100] In some embodiments of the present application, the chuck 605 is a three-jaw chuck.

[0101] In some embodiments of the present application, the second heating element 402 may be a heating block, and the second heating element 402 cooperates with the fixing screw 404 to control the coaxiality of the hollow copper tube and the nozzle.

[0102] For example, holes are drilled at appropriate positions on the outside of the second heating element 402 and the print head 203, and the dimensions are calculated so that the fixing screws 404 match the threaded holes of the second heating element 402 and the print head 203 and support the hollow copper tube 502 inside the print head 203, controlling the hollow copper tube 502 to be coaxial with the print head 203, thereby achieving a better spraying effect.

[0103] In some embodiments of the present application, when the above-mentioned device is used to perform printing in steps (3) and (6), the following steps are included:

[0104] (1) The first degradable polymer material / the third degradable polymer material is loaded into a barrel, and the temperatures of the first heating element and the second heating element are set according to the material properties to ensure that the material in the barrel will not be degraded due to excessive temperature, while ensuring the viscosity of the material so that the melted material can flow out smoothly;

[0105] (2) Fix the rotary axis platform to the XY axis base plate of the motion module, install the chuck on the fixed bracket, adjust the coaxiality of the ejector pin and the chuck, and use the chuck and ejector pin to fix the tubular printing substrate, i.e., the receiving substrate;

[0106] (3) Open the motion module, use the motion module to adjust the position of the print head, open the rotating shaft, first open the first air pressure valve, adjust the first air pressure gauge to control the flow rate of the molten material, then open the second air pressure valve and the second air pressure gauge to control the air flow rate in the hollow copper tube, and print according to the preset path;

[0107] (4) After printing is completed, the rotating shaft, the first and second air pressure valves, and the first and second heating elements are closed, and the print head is moved to the device origin.

[0108] In some embodiments of the present application, the biomimetic cross-scale multi-level gradient composite scaffold realizes a fully degradable dynamic regulation function through the construction and evaluation and regulation of the bioactive gradient functionalized surface in tissue repair.

[0109] In some other embodiments of the present application, a multi-level bionic 3D printed multi-level bionic cross-scale composite luminal stent is also provided, which is prepared by one of the above-mentioned preparation methods.

[0110] In some embodiments of the present application, the luminal stent includes a thin-walled three-layer tubular mesh stent, the bottom layer of the stent is an ordered fiber layer, which simulates the ordered cells of endothelial cells and is conducive to the circulation of body fluids; the middle layer of the luminal stent imitates the crossed and branched smooth muscle cells, and a mesh support structure is selected to provide core support function to ensure the overall structural stability of the stent; the outer layer of the luminal stent imitates loose connective tissue and selects disordered microfibers to reduce stress concentration on the tube wall tissue.

[0111] In some further embodiments of the present application, the above-mentioned luminal stent is also provided as a support device for use on body luminal tissues, wherein the luminal tissues are nerve conduits, vascular stents, esophageal stents, tracheal stents, urethral stents, bile duct stents and bone tissue engineering scaffolds.

[0112] In some embodiments of the present application, the luminal stent serves as a vascular stent to support a narrowed and occluded segment of a blood vessel, thereby reducing elastic retraction and reshaping of the blood vessel and maintaining smooth blood flow in the luminal cavity.

[0113] In some embodiments of the present application, the luminal stent is used as a tracheal stent, a bile duct stent, and an esophageal stent as an important palliative treatment for lung cancer, bile duct cancer, and esophageal cancer to relieve obstruction, improve quality of life, and prolong survival.

[0114] In some embodiments of the present application, a method for preparing a multi-stage biomimetic 3D printed composite luminal stent is provided, comprising the following steps:

[0115] (1) Reconstruct a personalized three-dimensional vascular stent model using CT and MRI scan images of the patient; conduct a comprehensive numerical analysis of the flow field changes and mechanical effects of the stent, optimize the stent blend material ratio, tube diameter, wire diameter, and support ring structure, and determine the structural parameters.

[0116] (2) Select poly (L-lactic acid) (PLLA) particles with a molecular weight of 100,000, clean them ultrasonically and place them in a drying oven at 40°C for 12 hours; then preheat them at 280°C for 2 hours to prepare for melt spraying.

[0117] (3) Using airflow field drive technology, melted left-handed polylactic acid (PLLA) fibers are sprayed onto a stainless steel substrate. Fiber orientation and porosity are controlled by adjusting substrate position and print height. The fiber diameter is 5-10 μm, the porosity is 40%-53%, and the thickness does not exceed 50 μm.

[0118] (4) Polycaprolactone (PCL) and polylactic acid (PLA) were mixed in a mass ratio of 5:5, dissolved in dichloromethane, and magnetically stirred at room temperature for 6 hours. The mixed solution was poured into a glass Petri dish and allowed to stand at 40°C for 4 hours to allow the solvent to evaporate, forming a solid blend material.

[0119] (5) Using electric field direct writing technology, a PCL / PLA copolymer mesh support structure was printed on the inner fiber structure. By adjusting the printing pressure and voltage, the line diameter was controlled to 100 μm and the gap was controlled to 500 μm, with a thickness not exceeding 100 μm. The nozzle temperature was adjusted to ensure a close connection with the inner layer.

[0120] (6) Using air flow field driven melt-blown spinning technology, PLLA disordered fibers are sprayed on the inner-middle layer structure. The fiber diameter is controlled at 0.5-5 μm and the thickness does not exceed 5 μm.

[0121] (7) The stainless steel substrate with the stent was immersed in a 0°C ultrapure ice-water mixture for 30 minutes to separate the stent. The stent was dried in a vacuum drying oven for 12 hours to obtain a luminal stent with an inner-middle-outer three-layer functional structure, which was used as a composite vascular stent.

[0122] In some embodiments of the present application, a method for preparing a multi-level biomimetic 3D printed cross-scale composite luminal stent is provided, comprising the following steps:

[0123] (1) Assess the degree and extent of nerve damage through MRI and electroneurography examinations of patients; construct a three-dimensional anatomical structure model of the lumen stent and optimize the diameter, length, and internal structure of the catheter.

[0124] (2) Using air-field driven melt-blown spinning technology, poly (L-lactic acid) (PLLA) was spun at 260°C with a collection distance of 15 cm. The fiber diameter was controlled within the range of 5-20 μm, forming a porous structure that promoted the attachment and growth of nerve cells.

[0125] (3) Using electric field direct writing technology, PCL (melting point 60°C) is heated to 180°C and a spiral support structure is printed on the inner layer of nanofibers using a precision nozzle. The spiral pitch is controlled to 80-100 μm and the wire diameter is 50-100 μm to provide sufficient mechanical strength.

[0126] (4) Using air flow field driven melt-blown spinning technology, PLLA disordered fibers are sprayed on the inner-middle layer structure. The fiber diameter is controlled at 0.25 μm and the thickness does not exceed 5 μm.

[0127] (5) Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were dissolved in phosphate buffered saline (PBS). The biological factor solution was evenly sprayed on the outer spinning layer by spraying, and then freeze-dried at 4°C for 12 hours.

[0128] (6) Separating the substrate to obtain a luminal stent having an inner-middle-outer three-layer functional structure, wherein the outer layer structure is loaded with biological factors.

[0129] In some embodiments of the present application, a method for preparing a multi-level biomimetic 3D printed cross-scale composite luminal stent is provided, comprising the following steps:

[0130] (1) Obtain accurate three-dimensional structural data of the trachea or bronchi through CT and bronchoscopy. Build a personalized tracheal stent model and optimize the stent's diameter, length, wall thickness, and pore structure to match the patient's specific lesion.

[0131] (2) Polycaprolactone (PCL) and poly(lactic-co-glycolic acid) (PLGA) were selected as the main materials, as these materials have good biocompatibility and controllable degradation. PCL and PLGA particles were treated in a vacuum drying oven at 50°C for 24 hours to remove residual moisture.

[0132] (3) Using air field driven melt-blown spinning technology with a collection distance of 20 cm, the fiber diameter is controlled at 5 μm to form a porous structure that simulates the tracheal mucosa and promotes the attachment and growth of epithelial cells.

[0133] (4) Using electric field direct writing technology, a PCL / PLA copolymer mesh support structure was printed on the inner fiber structure. The PCL / PLA mixed material (weight ratio 7:3) was heated to 190°C and a C-shaped ring support structure was printed using a precision nozzle. The C-shaped ring spacing was controlled to 5-8mm and the wire diameter was controlled to 300-500μm to provide sufficient radial support strength while maintaining axial flexibility.

[0134] (5) Using air field driven melt-blown spinning technology, the collection distance is 20 cm. The fiber diameter is controlled within the range of 0.5-5 μm, and the film thickness is controlled within the range of 50-100 μm to form a smooth outer surface and reduce tissue adhesion.

[0135] Other steps are the same as in Example 1.

[0136] The above description is merely a preferred embodiment of the present application and is not intended to limit the present application. Various modifications and variations are possible for those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present application shall be included within the scope of protection of the present application.

Claims

1. A method for preparing a multi-level bionic 3D printed cross-scale composite luminal stent, characterized in that: The following steps are involved: (1) Scan digital images of blood vessels to construct a three-dimensional anatomical structure model of the luminal stent. Perform a comprehensive numerical analysis of the stent flow field changes, liquid spreadability, and stent mechanical effects. Use the model to optimize the stent blend material ratio, tube diameter, wire diameter, and base structure to determine the structural parameters. (2) preheating the first degradable polymer material at a predetermined temperature for a predetermined time for melt spraying; (3) Applying airflow field to drive melt spinning technology, the degradable polymer material is jet-spinned on the substrate. By changing the placement of the substrate and the printing height, ordered inner-layer spun fibers with different orientations and porosities are obtained. As the inner layer of the vascular stent, the fiber diameter is controlled between 5-20 μm, the porosity is controlled between 37%-53%, and the thickness is controlled within 50 μm; (4) Weighing a second degradable polymer material, dissolving it in an organic solvent, pouring it into a container and allowing it to stand until the solvent evaporates, thereby obtaining a mixed second degradable polymer material; (5) Printing a mesh support structure of a middle support layer on a substrate having an inner layer of spun fibers using the mixed material obtained in step (4) by electric field direct writing technology; By adjusting the printing pressure and printing voltage, support layers with different wire diameters can be obtained to meet the support performance requirements of different lesion locations; the printing wire diameter range is 20-180μm, the printing gap range is between 60μm-2000μm, and the thickness is controlled within 100μm. The nozzle printing temperature is adjusted to ensure a tight connection between the inner layer of spun fibers and the middle layer of support layer; (6) using a third degradable polymer material and using an airflow field driven melt-blowing technology to perform outer layer spinning on the substrate of the inner-middle layer printed in step (5), thereby printing a vascular stent having an inner-middle-outer layer; the diameter of the spun fiber is controlled to be between 0.5-5 μm, and the thickness is controlled to be within 5 μm; (7) Soaking the substrate with the vascular stent in step (6) in an ultrapure ice-water mixture, and after the stent is separated from the substrate, drying the stent to obtain an inner-middle-outer three-layer luminal stent with a multifunctional layer.

2. The method for preparing a multi-stage bionic 3D printed cross-scale composite luminal stent according to claim 1, characterized in that: The first degradable polymer material is polylactic acid (PLA) or poly (L-lactic acid) (PLLA), the second degradable polymer material is polycaprolactone (PCL) / polylactic acid (PLA) copolymer, and the third degradable polymer material is poly (L-lactic acid) (PLLA).

3. The method for preparing a multi-stage bionic 3D printed cross-scale composite luminal stent according to claim 1, characterized in that: After the outer layer of spinning is prepared in step (6), nerve growth factor (NGF) and / or brain-derived neurotrophic factor (BDNF) are dissolved in phosphate buffered saline (PBS), and the biological factor solution is evenly loaded onto the outer layer of spinning by spraying.

4. The method for preparing a multi-stage bionic 3D printed cross-scale composite luminal stent according to claim 1, characterized in that: In the step (2), the preset temperature is 220-280° C., and the preset time is 1-2 hours; the organic solvent in the step (4) is dichloromethane (DCM); preferably, In step (4), polycaprolactone (PCL) particles and polylactic acid (PLA) powder are weighed, dried, and placed in a beaker containing dichloromethane (DCM). The solution is stirred at room temperature using a magnetic stirrer for 6 hours. The mixed solution is poured into a glass petri dish and allowed to stand at 40°C for 4 hours to allow the solvent to completely evaporate and the blended material to become a solid. The material after solvent evaporation is cut into strips for later use.

5. The method for preparing a multi-stage bionic 3D printed cross-scale composite luminal stent according to claim 1, characterized in that: In step (4), the support strength and support time are optimized by adjusting the ratio of polycaprolactone (PCL) and polylactic acid (PLA) according to the support requirements of the lesion site; the ratio of PCL:PLA ranges from 1:1 to 1:10, which can meet the support requirements of different lesion sites.

6. The method for preparing a multi-stage bionic 3D printed cross-scale composite luminal stent according to claim 1, characterized in that: In the steps (3) and (6), the device used for the airflow field driven meltblowing spinning technology includes: a motion module, a molten material printing nozzle module, a molten material feeding module, a temperature control module, a high-speed airflow control module, a rotating axis workbench, and a frame; The motion module includes an X-axis, a double Y-axis, and a Z-axis, wherein the double Y-axis is mounted on the frame, the X-axis is vertically mounted on the double Y-axis to form a gantry structure, and the Z-axis is mounted on the X-axis and remains perpendicular to the horizontal plane; The molten material printing nozzle module mainly includes a barrel, an adapter, and a printing nozzle. The adapter is equipped with a sealing ring and is assembled with the barrel and assembled on the Z axis of the motion module. The printing nozzle is connected to the barrel. The molten material feeding module is composed of a first air pressure valve, a first air pressure pump, a first air pressure gauge, and a three-way joint. The first air pressure pump is used to provide air pressure, and the air pressure display value is adjusted to adjust the discharge speed. The three-way joint is connected to the first air pressure gauge, the molten material printing nozzle module, and the high-speed airflow control module through hoses. The temperature control module includes a first heating element and a second heating element, wherein the first heating element is used to control the temperature of the molten material in the barrel; the second heating element is used to heat the temperature of the material at the print nozzle to prevent the material at the print nozzle from cooling and solidifying and clogging the nozzle, thereby better controlling the state of the material; The high-speed airflow control module includes a second air pressure valve, a second air pressure pump, a second air pressure gauge, and a hollow copper tube. To match the size of the print head, the hollow copper tube is selected to have a diameter smaller than the nozzle diameter. The hollow copper tube passes through a tee joint, an adapter, and a barrel all the way to the print head. The second air pressure gauge is used to control the flow rate of the high-speed airflow entering the hollow copper tube. The rotary workbench mainly includes a base plate, a bearing, two oppositely arranged fixed brackets, a motor, a chuck and an ejector. The two oppositely arranged fixed brackets are installed on the base plate, and the motor is installed at the same time. The chucks at both ends are respectively installed on the fixed brackets at both ends through bearings. The chuck is installed on one side of the chuck and cooperates with the motor through a coupling. The chuck on the other side is installed with the ejector to align and fix the tubular printing substrate.

7. The method for preparing a multi-stage bionic 3D printed cross-scale composite luminal stent according to claim 6, characterized in that: When the above device is used to print steps (3) and (6), the following steps are included: (1) The first degradable polymer material / the third degradable polymer material is loaded into a barrel, and the temperatures of the first heating element and the second heating element are set according to the material properties to ensure that the material in the barrel will not be degraded due to excessive temperature, while ensuring the viscosity of the material so that the melted material can flow out smoothly; (2) Fix the rotary axis platform to the XY axis base plate of the motion module, install the chuck on the fixed bracket, adjust the coaxiality of the ejector pin and the chuck, and use the chuck and ejector pin to fix the tubular printing substrate, i.e., the receiving substrate; (3) Open the motion module, use the motion module to adjust the position of the print head, open the rotating shaft, first open the first air pressure valve, adjust the first air pressure gauge to control the flow rate of the molten material, then open the second air pressure valve and the second air pressure gauge to control the air flow rate in the hollow copper tube, and print according to the preset path; (4) After printing is completed, the rotating shaft, the first and second air pressure valves, and the first and second heating elements are closed, and the print head is moved to the device origin.

8. A multi-level bionic 3D printed multi-level bionic cross-scale composite luminal stent, characterized by: Prepared by the preparation method according to any one of claims 1 to 7.

9. A multi-level bionic 3D printed multi-level bionic cross-scale composite luminal stent, characterized in that: Prepared by the preparation method described in any one of claims 1-7; the luminal stent includes a thin-walled three-layer tubular mesh stent, the bottom layer of the stent is an ordered fiber layer, which simulates the ordered cells of endothelial cells and is conducive to the circulation of body fluids; the middle layer of the luminal stent imitates the crossed and branched smooth muscle cells, and a mesh support structure is selected to provide a core support function to ensure the overall structural stability of the stent; the outer layer of the luminal stent imitates loose connective tissue and selects disordered microfibers to reduce stress concentration on the tube wall tissue.

10. Use of the luminal stent according to claim 8 as a support device on body luminal tissues, wherein the luminal tissues are nerve conduits, vascular stents, esophageal stents, tracheal stents, urethral stents, bile duct stents and bone tissue engineering scaffolds.

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