Biocompatible and high-toughness degradable polymer base material with autonomous memory recovery and development, preparation method and application

Abstract

The invention discloses a biodegradable polymer base material with self-memory recovery, development, biocompatibility and high toughness, a preparation method and application. The preparation method comprises the following steps: uniformly stirring 30-80 parts by mass of the elastic memory unit, 10-20 parts by mass of the contrast agent and 10-50 parts by mass of the reinforced fiber to obtain a mixture; and putting the mixture into a screw machine, and extruding through a screw to obtain the degradable polymer base material with the required shape and size. Wherein the elastic memory unit, the contrast agent and the reinforced fibers are all degradable or can be absorbed by a human body, and have good biocompatibility. The degradable polymer base material provided by the technical scheme of the invention is simple in preparation process, the prepared base material has good memory resilience, developability, high toughness, biocompatibility and the like, and all the components are easy to degrade or absorb, so that performance balance is achieved. And finally, a vascular disease medical instrument product prepared on the basis of the base material has excellent application performance in a human body.

Description

Technical Field

[0001] The present application relates to the field of medical device technology, and in particular to a biodegradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness, a preparation method and application thereof. Background Art

[0002] The main treatments for patients with congenital heart disease are currently thoracotomy and percutaneous interventional surgery. In percutaneous interventional surgery, implantation of NiTi alloy occluders under X-ray imaging is the current common procedure. The long-term safety of NiTi alloy occluders is questionable due to the metal corrosion of its metal material, nickel ion precipitation, nickel ion allergy in a few patients, conduction block, and other issues. These issues are all related to the non-degradability of the occluder itself. Based on this, degradable occluders have emerged due to their huge potential.

[0003] The materials of degradable occluders are divided into degradable metals and degradable polymer materials. Because existing degradable metals such as magnesium alloys, zinc alloys, and iron alloys can only meet the requirements of developability, but cannot meet the requirements of memory recovery and easy weaving and shaping, the current occluder product materials are still mainly concentrated on degradable polymer materials. However, the current degradable polymer materials have poor biocompatibility, and will cause obvious inflammation, metabolic toxicity, and seriously affect the crawling of tissue endothelial cells in the human body. At the same time, the various shapes of substrates made of degradable polymers are brittle and have limited elasticity, which will affect the elastic deformation of the material and also bring difficulties to the processing of the substrate.

[0004] Therefore, it is necessary to research and develop the preparation of the substrate for the occluder in order to balance the various performance requirements of the occluder. Summary of the invention

[0005] The present application provides a biodegradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness, a preparation method and application, aiming to solve the problem that the occluder in the prior art is not compatible with the memory recovery, development, biocompatibility and easy processing properties of the implant product due to material selection.

[0006] To achieve the above objectives, the present application proposes a method for preparing a biodegradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness. The preparation method comprises the following steps:

[0007] By weight, 30 to 80 parts of elastic memory unit, 10 to 20 parts of contrast agent and 10 to 50 parts of reinforcing fiber are uniformly stirred to obtain a mixture;

[0008] The mixture is placed in a screw machine, and a degradable polymer substrate of a desired shape and size is obtained by screw extrusion;

[0009] The elastic memory unit, the contrast agent and the reinforcing fiber are all made of materials that are degradable or absorbable by the human body and have good biocompatibility.

[0010] In some embodiments, 60 parts of elastic memory unit, 15 parts of contrast agent and 25 parts of reinforcing fiber are mixed uniformly by weight to obtain a mixture.

[0011] In some embodiments, the stirring speed is 100 to 300 rpm, and the stirring time is 15 to 30 min.

[0012] In some embodiments, the elastic memory unit is at least one of PLCL copolymer, PU copolymer, polycarbonate, and aliphatic polyester elastomer.

[0013] In some embodiments, the contrast agent is at least one of iohexol, iosopeptidol, iovisol, iopromide, and iodixanol.

[0014] In some embodiments, the reinforcing fiber is at least one of bamboo fiber, silk fibroin fiber, polylactic acid fiber, and polyglycolic acid fiber.

[0015] In some embodiments, the length of the reinforcing fibers is 0.1 to 10 mm.

[0016] In some embodiments, the degradable polymer substrate is in the shape of a filament or a sheet.

[0017] The present application also proposes a degradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness. The degradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness is prepared by the preparation method as described above.

[0018] The present application also proposes the use of the above-mentioned degradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness in medical device products for vascular diseases.

[0019] The technical solution of this application proposes a degradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness, a preparation method and application. The preparation method comprises: according to the mass content, 30 to 80 parts of elastic memory unit, 10 to 20 parts of contrast agent and 10 to 50 parts of reinforcing fiber are stirred evenly to obtain a mixture; the mixture is placed in a screw machine, and the degradable polymer substrate of the required shape and size is obtained by screw extrusion. Among them, the elastic memory unit, contrast agent and reinforcing fiber are all degradable or absorbable materials of the human body, and have good biocompatibility. The preparation method provided by the technical solution of this application can form the required degradable polymer substrate by physical mixing of elastic memory unit, contrast agent and reinforcing fiber, and then extruding by screw machine, which has simple process and quick preparation. And each component of the prepared substrate is a material that is degradable or absorbable by the human body, and based on the material properties of each component in the substrate, the substrate has good memory recovery, development, high toughness and biocompatibility, so as to achieve performance balance. And finally, the vascular disease medical device product prepared based on the substrate has excellent application performance in the human body. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the prior art descriptions are briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative work, among which:

[0021] Figure 1 This is a schematic diagram of a process for preparing a degradable polymer substrate according to an embodiment of the present application;

[0022] Figure 2 This is a schematic structural diagram of a woven occluder according to an embodiment of the present application. DETAILED DESCRIPTION

[0023] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0024] See also Figure 1 As shown, the present application proposes a method for preparing a biodegradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness. The preparation method comprises the steps of:

[0025] S10, mixing 30 to 80 parts of elastic memory units, 10 to 20 parts of contrast agents and 10 to 50 parts of reinforcing fibers uniformly by weight to obtain a mixture.

[0026] In this step, the elastic memory unit, contrast agent and reinforcing fiber are all made of materials that are degradable or absorbable by the human body and have good biocompatibility.

[0027] The elastic memory unit as the main raw material is intended to achieve shape memory recovery. Exemplarily, the elastic memory unit is at least one of PLCL copolymer, PU copolymer, polycarbonate, and aliphatic polyester elastomer. When subjected to external stimuli, such as temperature changes or strain, the molecular chains of these materials will undergo reversible conformational changes or phase transitions, resulting in changes in shape. When the stimulus is removed, the molecular chains will return to their original state, thereby achieving shape memory recovery.

[0028] The contrast agent is used to display the position and morphology of materials in medical monitoring, and can realize dual calibration of X-ray equipment and ultrasound equipment. Exemplarily, the contrast agent is at least one of iohexol, iosopeptidol, iovisol, iopromide, and iodixanol.

[0029] The reinforcing fiber has the function of improving the mechanical strength and stability of the substrate. By compounding with the elastic memory unit, the properties of the produced polymer substrate such as tensile strength and elongation at break can be adjusted, while reducing the cost of raw materials. Exemplarily, the reinforcing fiber includes at least one of bamboo fiber, silk fibroin fiber, polylactic acid fiber, and polyglycolic acid fiber.

[0030] Then, the elastic memory unit, contrast agent and reinforcing fiber are mixed in a preset ratio according to the mass content, and the specific ratio can be adjusted according to the performance and application scenario of the substrate to be prepared, so as to meet the preset degradable cycle of the substrate and achieve a unified balance between the mechanical properties of the degradable substrate and the material product. In a preferred embodiment, 60 parts of the elastic memory unit, 15 parts of the contrast agent and 25 parts of the reinforcing fiber are stirred uniformly according to the mass content to obtain a mixture.

[0031] In this mixing step, a stirring device such as a high-speed mixer, a planetary mixer, etc. can be used to mix and stir the above components to ensure that each component is fully dispersed and fused to form a uniform mixture. Among them, parameters such as stirring time, stirring speed and stirring temperature should be adjusted according to the characteristics of the components and the desired mixing effect. In general, the stirring time should be long enough to ensure that the mixture reaches a uniform state and avoid excessive stirring to cause material degradation. Exemplarily, the stirring speed is 100 to 300 rpm at room temperature and the stirring time is 15 to 30 minutes. The order in which the components are mixed can be to blend the elastic memory unit with the reinforcing fiber first, and then add the contrast agent to mix, or the elastic memory unit, the contrast agent and the reinforcing fiber can be added at the same time and blended together.

[0032] Furthermore, before mixing the components, the components may be pretreated, such as drying and crushing the reinforcing fibers to make the length of the reinforcing fibers 0.1 to 10 mm, so as to improve their dispersibility and mixing effect.

[0033] It is understandable that the elastic memory unit in this application can be synthesized by but not limited to the following methods: preparing prepolymer or copolymer finished products in the form of melt polycondensation, melt extrusion, monomer crosslinking, catalytic copolymerization, etc., or subsequently modifying, grafting, curing, coupling, and introducing topological structures to meet performance requirements. Among them, the elastic memory unit can complete the synthesis of monomers by itself with laboratory instruments and professionals, or it can be commissioned to a professional manufacturer to synthesize according to the monomer ratio; contrast agents are mature reagents for medical clinical applications, and reinforcing fibers can be directly purchased by professional manufacturers on the market, which greatly reduces the difficulty of obtaining raw materials for preparation.

[0034] S20, putting the mixture into a screw machine, and obtaining a degradable polymer substrate of a desired shape and size through screw extrusion.

[0035] In this step, it is preferred to use a twin-screw extruder to extrude the mixture. During the process, by the rotation of the screw, the mixture is conveyed, compressed, melted and extruded in the gap between the screw and the barrel, not only subjecting the mixture to strong shearing and friction, but also achieving the mixing and homogenization of the components, and by gradually reducing the depth of the groove, the components are compressed so that their density and temperature are gradually increased, and finally a molten state is reached. Thus, the polymer solution in the further molten state is extruded through the mold of the screw head to form a degradable polymer substrate of a desired shape and size, and the stability of its shape and size is ensured after cooling and solidification.

[0036] Among them, the degradable polymer substrate is in the shape of a wire or a sheet film, which has broad application prospects and market demand.

[0037] The present application proposes a degradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness, and the degradable polymer substrate is prepared by the above preparation method. Based on the above characteristics of each component, the polymer substrate prepared in the present application has the properties of degradability, memory recovery, development, biocompatibility and high toughness, so as to better meet the product performance requirements.

[0038] The present application also provides an application of a degradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness in medical device products for vascular diseases. For example, occluders, degradable patches, neurointervention products, coronary and peripheral implant products, etc. can be prepared based on the degradable polymer substrate. Furthermore, the present application forms filaments through extrusion, and the filaments can be woven into structures such as ventricular septal defect occluders, patent foramen ovale occluders, atrial septal defect occluders and left atrial appendage occluders. For example, the patent foramen ovale occluder mainly includes two disks woven with filaments located in the left and right atria, and the two disks are connected at the waist. A flow-blocking membrane is also provided inside. These basic structural combinations work together to block the defect and prevent blood shunting. Figure 2 Shown is a schematic diagram of the structure of the occluder formed by weaving, which is a "tension-gaining structural modeling and waist design".

[0039] Based on this, the structural design matched in the application makes the structural design better conform to the function of the substrate, and the structural design of the manufactured product is in an expanded state, which is the starting point. Before the product is implanted or intervened in the human body, the disk is in a contracted state, that is, the process point. After being implanted or intervened in the human body through a sheath or a dedicated delivery system, it can basically return to the expanded state of the preset starting point under the stimulation of temperature (near body temperature) or force, completing the memory recovery function of the product in the body.

[0040] The technical solution of the present application further provides various preparation examples of a degradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness, including:

[0041] Example 1

[0042] a) By weight, 30 parts of elastic memory unit (PLCL copolymer), 20 parts of contrast agent (iopromide) and 50 parts of reinforcing fiber (bamboo fiber) are uniformly stirred to obtain a mixture.

[0043] b) putting the mixture into a screw machine and obtaining a degradable polymer substrate of desired shape and size through screw extrusion.

[0044] Example 2

[0045] a) By weight, 60 parts of elastic memory unit (PLCL copolymer), 15 parts of contrast agent (iopromide) and 15 parts of reinforcing fiber (bamboo fiber) are uniformly stirred to obtain a mixture.

[0046] b) putting the mixture into a screw machine and obtaining a degradable polymer substrate of desired shape and size through screw extrusion.

[0047] Example 3

[0048] a) By weight, 80 parts of elastic memory unit (PLCL copolymer), 10 parts of contrast agent (iopromide) and 10 parts of reinforcing fiber (bamboo fiber) are uniformly stirred to obtain a mixture.

[0049] b) putting the mixture into a screw machine and obtaining a degradable polymer substrate of desired shape and size through screw extrusion.

[0050] Example 4

[0051] a) By weight, 60 parts of elastic memory units (PLCL copolymers, PU copolymers and polycarbonates), 15 parts of contrast agents (iopromide) and 15 parts of reinforcing fibers (bamboo fibers) were uniformly stirred to obtain a mixture.

[0052] b) putting the mixture into a screw machine and obtaining a degradable polymer substrate of desired shape and size through screw extrusion.

[0053] Example 5

[0054] a) By weight, 60 parts of elastic memory unit (PLCL copolymer), 10 parts of contrast agent (iopromide, iohexol and iosopeptidol) and 10 parts of reinforcing fiber (bamboo fiber) are uniformly stirred to obtain a mixture.

[0055] b) putting the mixture into a screw machine and obtaining a degradable polymer substrate of desired shape and size through screw extrusion.

[0056] Example 6

[0057] a) By weight, 60 parts of elastic memory unit (PLCL copolymer), 15 parts of contrast agent (iopromide) and 15 parts of reinforcing fiber (bamboo fiber, silk fibroin fiber and polylactic acid fiber) were stirred uniformly to obtain a mixture.

[0058] b) putting the mixture into a screw machine and obtaining a degradable polymer substrate of desired shape and size through screw extrusion.

[0059] Example 7

[0060] a) By weight, 60 parts of elastic memory units (PLCL copolymers, PU copolymers and polycarbonates), 15 parts of contrast agents (iopromide, iohexol and iosopeptidol) and 15 parts of reinforcing fibers (bamboo fibers, silk fibroin fibers and polylactic acid fibers) were uniformly stirred to obtain a mixture.

[0061] b) putting the mixture into a screw machine and obtaining a degradable polymer substrate of desired shape and size through screw extrusion.

[0062] Comparative Example

[0063] The substrate is a blend of polydioxanone, polycaprolactone, polyglycolic acid, polylactic acid-co-glycolic acid or amorphous polylactic acid, L-polylactic acid and D-polylactic acid.

[0064] The present application further tests the performance of the substrates prepared in the above embodiments and comparative examples; including:

[0065] Disk surface recovery rate test: Test according to the following test method. At a temperature of 37±2°C, the diameter of the polymer filament braided disk is measured by a vernier caliper as A. It is loaded into a sheath of a certain size under cold water (0-6°C), and then the disk is released at a temperature of 37±2°C. After the shape is restored, the disk diameter is measured by a vernier caliper as B. The disk surface recovery rate is obtained by B / A. The memory recovery rate of the products in each embodiment and comparative example is evaluated. Evaluation criteria: Poor - disk surface recovery rate is less than 60%; General - disk surface recovery rate is 60% to 90%; Good - disk surface recovery rate is above 90%.

[0066] Development test: Based on the standard number YY / T 0586-2016, the X-ray opacity test method for medical polymer products was carried out to evaluate the development effect of the substrate in each embodiment and comparative example. Evaluation criteria: poor - unable to develop; general - only one of the X-ray device and the ultrasonic device can be satisfied; good - dual calibration of the X-ray device and the ultrasonic device is achieved.

[0067] Degradability test: Test according to the following test method. Take a braided wire of a certain outer diameter for tensile strength performance test and record the value as A. At a temperature of 37±2°C and a pH value of 7.4±0.2, take a plurality of unused braided wires of this size and fix them in a special in vitro simulated body fluid (such as PBS body fluid) circulation device. When the time nodes of 1 month, 3 months, and 6 months are reached, take them out and perform tensile strength test and record the value as B. The mechanical property (tensile strength) retention rate of the disk wire under the degradation cycle is obtained by B / A. The degradation performance of the substrate in each embodiment and comparative example is evaluated. Evaluation criteria: Poor-the mechanical properties of the degraded substrate are maintained below 50% in the first 6 months; General-the mechanical properties of the degraded substrate are maintained at 50% to 70% in the first 6 months; Good-the mechanical properties of the degraded substrate are maintained above 70% in 6 months.

[0068] Biocompatibility test: Based on the standard number GB / T 16886.5-2017, an in vitro cytotoxicity test was performed to evaluate the in vitro cytotoxicity of the substrates in each embodiment and comparative example. Evaluation criteria: poor - cytotoxicity greater than 2; fair - cytotoxicity between 1 and 2; good - cytotoxicity not greater than 1.

[0069] High toughness / processability test: The polymer tensile properties test was conducted with reference to standard number ISO 527-1-2019 to evaluate the mechanical or processing properties of the substrate in each embodiment and comparative example. Evaluation criteria: Poor - elongation less than 100% / breaking force less than 30N; General - elongation 100% to 300% / breaking force 30N to 40N; Good - elongation not less than 500% / breaking force not less than 50N.

[0070] After testing the substrates prepared in Examples 1-7 and the comparative example respectively by the above test method, the resulting benefit comparison is shown in Table 1.

[0071] Table 1

[0072]

[0073] It can be seen from the test results shown in Table 1 that the degradable polymer substrate prepared by the preparation method of the present application and based on the parameter selection requested for protection in the present application has good performance in disk surface recovery rate, development, degradability, biocompatibility and processability, thereby balancing the performance requirements of the degradable polymer substrate and meeting the application of the manufactured product in the human body.

[0074] The above description is only a partial or preferred embodiment of the present application. Neither the text nor the drawings can limit the scope of protection of the present application. All equivalent structural changes made using the contents of the present application specification and drawings under the overall concept of the present application, or direct / indirect application in other related technical fields are included in the scope of protection of the present application.

Claims

1. A method for preparing a biodegradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness, characterized in that: The preparation method comprises the steps of: By weight, 30 to 80 parts of elastic memory unit, 10 to 20 parts of contrast agent and 10 to 50 parts of reinforcing fiber are uniformly stirred to obtain a mixture; The mixture is placed in a screw machine, and a degradable polymer substrate of a desired shape and size is obtained by screw extrusion; The elastic memory unit, the contrast agent and the reinforcing fiber are all made of materials that are degradable or absorbable by the human body and have good biocompatibility.

2. The method for preparing a biodegradable polymer substrate having autonomous memory recovery, development, biocompatibility and high toughness according to claim 1, characterized in that: 60 parts of elastic memory units, 15 parts of contrast agents and 25 parts of reinforcing fibers were uniformly stirred by mass to obtain a mixture.

3. The method for preparing a biodegradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness according to claim 2, characterized in that: The stirring speed is 100-300 rpm, and the stirring time is 15-30 min.

4. The method for preparing a biodegradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness according to claim 1, characterized in that: The elastic memory unit is at least one of PLCL copolymer, PU copolymer, polycarbonate, and aliphatic polyester elastomer.

5. The method for preparing a biodegradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness according to claim 1, characterized in that: The contrast agent is at least one of iohexol, iodixanol, iovisol, iopromide, and iodixanol.

6. The method for preparing a biodegradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness according to claim 1, characterized in that: The reinforcing fiber is at least one of bamboo fiber, silk fibroin fiber, polylactic acid fiber and polyglycolic acid fiber.

7. The method for preparing a biodegradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness according to claim 6, characterized in that: The length of the reinforcing fiber is 0.1 to 10 mm.

8. The method for preparing a biodegradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness according to claim 1, characterized in that: The degradable polymer substrate is in the shape of a filament or a sheet film.

9. A biodegradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness, characterized in that: The method is prepared according to any one of claims 1 to 8.

10. Use of the biodegradable polymer substrate with autonomous memory recovery, development, biocompatibility and high toughness as claimed in claim 9 in medical device products for vascular diseases.

Images