WO2022000322A1

WO2022000322A1 - Developing composite material and preparation method therefor and use thereof, and implantable and interventional medical instrument and preparation method therefor

Info

Publication number: WO2022000322A1
Application number: PCT/CN2020/099501
Authority: WO
Inventors: 赵清华; 冯汉卿; 吴斯倞; 刘青; 赵庆洪; 穆士卿
Original assignee: 北京阿迈特医疗器械有限公司
Priority date: 2020-06-30
Filing date: 2020-06-30
Publication date: 2022-01-06

Abstract

A developing composite material and a preparation method therefor. The developing composite material is prepared from the following raw materials in percentage by weight: 20%-80% of a non-developing high-molecular polymer, 80%-20% of an impermeability improver, and 0-10% of a surface active agent. When the composite material is prepared, a melting stirrer or an extruder is used for material mixing or even mixing in a solvent, the solvent is removed, and then the composite material is granulated or extruded into filaments or used for preparing a medical instrument. Further, also disclosed are a use of the composite material, and an implantable and interventional medical instrument using the composite material and a preparation method therefor. The composite material is filamentous and thus has a good developing effect, and the developing composite material which has a developer content exceeding 50% and is suitable for an extrusion process can be prepared by utilizing the method for the composite material. The medical instrument prepared from the composite material has a good developing effect and is beneficial to intraoperative operation and postoperative follow-up.

Description

Development composite material, preparation method and use thereof, implantable and interventional medical device and preparation method thereof

technical field

The invention belongs to composite materials for medical devices, in particular to developing composite materials, and also relates to a preparation method and application of the composite materials, as well as a vascular embolization device or a vascular stent or occluder and a preparation method thereof.

Background technique

Aneurysm is a disease caused by changes in the structure and hemodynamics of the vascular wall caused by various factors. The wall is thin, and once ruptured, the patient is at risk of life.

The previous treatment was mainly based on surgical clipping and artificial blood vessel replacement. In the past half century, minimally invasive endovascular embolization has emerged. The intervention process is simple, the patient has less bleeding, and the postoperative recovery is fast. In 1974, Serbineko first used a detachable balloon to embolize intracranial aneurysms. At present, coil embolization has been widely used. By implanting several metal coils into the hemangioma, the coils block the blood in the hemangioma. And promote the agglutination of blood components in the aneurysm, and form a thrombus in the aneurysm, thereby isolating the aneurysm from the blood circulation of the parent artery, and achieving the therapeutic purpose of reducing the impact of blood flow on the aneurysm wall and preventing the rupture of the aneurysm.

The spring coils currently on the market are mainly metal coils. Representative products include COOK's Flipper, Nester, MReye, Embolization Coils; Boston Scientific's Interlock-35, Fibered IDC; MicroVention's MicroPlex, etc. Although the above metal coils have good developing performance, the material of such coils cannot be degraded and absorbed by the human body, and will stay in the human body permanently after being implanted into the human body, which will cause strong MRI or CT examination of the hemangioma. Artifacts, image analysis of hemangioma and its surrounding tissue cannot be performed, and the long-term existence of metal implants will bring long-term risks; and once it recurs, it is difficult to reprocess; at the same time, the difference between the physical and mechanical properties of metal materials and tissues is compared. Large, it is not easy to form randomly against the wall. In view of this, researchers began to consider polymer embolization devices that can be degraded and absorbed by the body. This kind of embolization device can effectively fill hemangioma after being implanted into the human body, rapidly form a thrombus, and then gradually degrade, absorb and disappear in the human body.

Implantable metal medical devices are generally X-ray developable because the material blocks the radiation. However, polymer devices are generally transparent to X-rays and do not develop under X-rays. Doctors cannot accurately position and fill non-developing devices during the implantation process, which increases the difficulty of surgery and may cause harm to patients. It increases the risk of surgery; it is not easy to locate during the postoperative examination, which increases the difficulty of follow-up. Therefore, it is of great significance to improve the developing properties of polymer medical devices.

The preparation method of the existing developable polymer material is mainly divided into physical method and chemical method, and its main shortcoming is:

1. When the developable polymer composite material is prepared by physical mixing, it is prone to the shortcomings of uneven mixing, poor stability of the developer and easy falling off, which leads to the easy occurrence of holes and the decline of mechanical properties in the material.

2. When the developable polymer composite material is prepared by chemical methods, the synthesis process is complicated and difficult to control. The use of a large amount of organic solvents in the synthesis process may easily cause environmental pollution and solvent residues may bring harm to the health of patients.

The Canadian invention patent with the publication number CA2579619(A1) provides a preparation method of a developable polymer material. This patent combines the developing iodine element to the polymer molecular chain through the chemical method of covalent bonding. This technology can make the polymers synthesized by this technology have developability, but the synthesis process is complicated and difficult to control, and the use of a large amount of organic solvents in the synthesis process may easily cause environmental pollution and solvent residues may bring harm to patients' health.

The Chinese invention patent application with publication number CN101700418A discloses a developable and degradable polymer composite material and a preparation method thereof. The binding tape is composed of a developer and a biodegradable polymer with high strength and elasticity. Preparation method: The biodegradable polymer and the developer are mixed and dissolved in the solvent, fully stirred and dissolved to obtain a uniform solution, ultrasonic treatment makes the developer evenly dispersed in the solution, and then the solution is cast into a long strip of mold, placed in Allow the solvent to fully evaporate in an outdoor environment. The method of the invention is simple to operate, does not need complex equipment, can be mass-produced, and has low preparation cost; the medical strapping tape prepared by the invention can be biodegraded in the body, so as to avoid secondary injury to the patient and achieve better therapeutic effect; The medical strapping band prepared by the invention can be radiographed by X-ray, which can be used to observe the biodegradation of the medical strapping strap after being implanted in the body. However, for small-sized medical devices, such as filamentous treatment devices, the developing effect is very poor, and it is almost impossible to develop. In order to enhance the development effect, the amount of the developer can be increased, but if the content of the radiopacity modifier exceeds 20%, the medical device cannot be prepared by extrusion molding.

SUMMARY OF THE INVENTION

In order to solve the defect that the existing developing materials cannot develop well for small-sized medical instruments in the prior art, the present invention provides a developing composite material, which also has a good developing effect for small-sized medical instruments.

In order to achieve the above purpose, the present invention adopts the following technical scheme: the developing composite material is made of the following raw materials by weight: 20%-80% of non-developing high molecular polymer, 80%-20% of impermeability modifier and surface activated dose 0-10%.

Preferably, the non-developing high molecular polymer is a thermoplastic polymer.

Preferably in any of the above schemes, the non-developing high molecular polymer is selected from polylactic acid (PLA), left-handed polylactic acid (PLLA), right-handed polylactic acid (PDLA), polyethylene glycol-polyglycolic acid (PGA) , Polycaprolactone (PCL), Polyethylene Glycol (PEG), Polyanhydride, Polyhydroxyalkanoate (PHA), Polydioxanone, Polyiminocarbonate, Polyfumaric Acid, Polycarbonate One or more copolymers or mixtures of esters, polyurethanes, polyphenylene olefins, polyolefins, and polychlorinated olefins.

Preferably in any of the above solutions, the radiopacity modifier is selected from one or more of the following: calcium phosphate, bismuth subcarbonate, iodine compounds used as contrast agents, barium sulfate, zirconium dioxide, strontium halide Wait.

It is preferred that any of the above-mentioned schemes is that the surfactant is selected from the following one or more: sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monooleate laurate, polyethylene glycol tert-octyl phenyl ether, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), poly(propylene glycol)-block-poly( ethylene glycol)-block-poly(propylene glycol) and other polyglycol-based polymers, polyoxyalkylenes, and the like.

In any of the above schemes, preferably, in terms of weight percentage, the developing composite material is composed of: 20%-79.99% of non-developing high molecular polymer, 79.99%-20% of impermeability modifier and 0.01%-20% of surfactant 10%.

Preferably in any of the above solutions, in terms of percentage by weight, the developing composite material is composed of: 20%-79% of non-developing high molecular polymer, 79%-20% of impermeability modifier and 1%-20% of surfactant 5%.

Preferably in any of the above solutions, the developing composite material is composed of: 30-70% non-developing high molecular polymer, 20-69% opacity modifier and 1-10% surfactant in weight percentage.

In any of the above solutions, preferably, the developing composite material is composed of 30-60% non-developing high molecular polymer, 30-65% opacity modifier and 1-5% surfactant in weight percentage.

Preferably in any of the above solutions, the developing composite material is composed of: 42-45% of non-developing high molecular polymer, 52-55% of impermeability modifier and 3-5% of surfactant.

Preferably in any of the above solutions, the developing composite material is: 45% non-developing high molecular polymer, 50% radiopacity modifier and 5% surfactant.

Preferably in any of the above solutions, the developing composite material is composed of: 45% non-developing high molecular polymer, 52% radiopacity modifier and 3% surfactant.

Preferred embodiments of the present invention relate to X-ray imageable polymer composites for use in the manufacture of medical devices (eg, vascular embolization devices, vascular stents, occluders, etc.).

In order to overcome the problem that the composite material cannot be suitable for extrusion molding when the developer content is higher than 20% in the prior method, the second aspect of the present invention provides a preparation method of the developing polymer, the steps are as follows:

(1) Prepare raw materials according to the formula;

(2) Mixing all the raw materials together, carrying out melting stirring or extrusion or granulation, or mixing evenly in a solvent and then extruding or granulating to obtain the developing composite material.

By using the preparation method of the developing composite material of the present invention, the developing composite material with the developer exceeding 50% can be prepared, which is suitable for the extrusion molding process.

In a third aspect, the present invention provides the use of the developing polymer in the preparation of implantable and interventional medical devices.

Preferably, the implantable and interventional medical device is of small size, for example, the minimum size of metal coils is 0.014 inches (355.6 microns).

Preferably in any of the above solutions, the implantable and interventional medical device is an embolization device, such as a coil, a natural orifice stent, a thrombectomy device, a drug release device, a covered stent, a vascular stent or an occluder.

Preferably in any of the above solutions, the composite material is used to prepare a vascular stent or an occluder.

In a fourth aspect, the present invention also provides an implantable and interventional medical device, which is prepared by using the developing composite material obtained in the first aspect or the second aspect of the present invention.

Preferably, the wire diameter (diameter) of the implantable and interventional medical device is 0.08-1 mm.

In any of the above solutions, preferably, the surface of the implantable and interventional medical device can be wrapped with degradable polymer cilia to promote blood coagulation.

Preferably in any of the above solutions, the surface of the implantable and interventional medical device is not entangled with degradable polymer cilia.

In any of the above solutions, it is preferable that the surface of the implantable and interventional medical device is covered with a degradable/non-degradable polymer membrane that can easily absorb blood components, so as to optimize the delivery.

Preferably in any of the above solutions, the degradable/non-degradable polymer membrane can be covered by dipping, spraying or electrospinning.

Preferably in any of the above solutions, the degradable/non-degradable polymer film contains or does not contain a drug with a high embolization effect.

In any of the above solutions, it is preferable that the surface of the implantable and interventional medical device is not covered with a degradable/non-degradable polymer film that can easily absorb blood components.

Preferably in any of the above solutions, the implantable and interventional medical device includes an embolization device, a coil, a vascular stent, a natural orifice stent, a thrombectomy device, a drug release device, a stent-graft or an occluder.

In a fifth aspect, the present invention provides a method for preparing the embolization device described in the fourth aspect, the steps are as follows:

(i) preparing the developing composite;

(ii) The composite material is prepared into a filament with a certain diameter (0.08-1 mm as mentioned above) by using the method of melt extrusion into filament; then the obtained filament is wound and fixed in a certain diameter On the shaped object of diameter and length, the shaped object and the wire are then placed in a heating device with a certain temperature for heat setting. The heat-set shaped object and filament are taken out and cooled to room temperature, and the filament is removed from the shaped object to obtain the desired developable device; or,

(iii) Using a four-axis rapid prototyping system as a manufacturing equipment, including the following steps:

1) according to the structure of the embolization device to be prepared, prepare the shaped mold;

2) A program for designing the deposition pattern of polymer fibers by computer;

3) Fixing the shaped mold to the position of the rotating rod of the fourth axis system of the four-axis rapid prototyping system, so that it can be forward or reverse with the fourth axis rotating rod under the control of the computer control system. reverse rotation;

4) adding the composite material of the thermoplastic polymer prepared above, the radiopaque modifier and the surfactant into the distribution system of the four-axis rapid prototyping system;

5) According to the program designed in step 2), the XYZ positioning system and the fourth axis system are controlled by the computer control system, so that the distribution system can accurately extrude the polymer fibers according to the pre-designed deposition pattern of the polymer fibers, and deposit them on the fourth axis The specific location of the rotatable shaped tire or directly deposited on the rotating rod, thereby producing the plug device of specific size and structure;

6) Remove the plugging device prepared in step 5) from the shaped tire.

Preferably, the four-axis rapid prototyping system includes:

(i) the base;

(ii) a three-axis X-Y-Z positioning system attached to the base, wherein the X-Y-Z positioning system defines the X, Y, Z directions, respectively;

(iii) a dispensing system mounted on and moved by said X-Y-Z positioning system, said dispensing system containing an extrusion head;

(iv) a fourth axis system connected to the base, comprising a rotating rod connected to the base below the extrusion head, wherein the rotating rod can be forward or reversed about its axis rotate; the central axis of the rotating rod is parallel to the Y axis; and

(v) A computer control system, which can precisely control the XYZ positioning system according to the set program to precisely control the movement of the extrusion head of the distribution system in the X, Y, Z directions, and precisely control the fourth axis system. The rotation of the rotating rod about its axis.

Preferably in any of the above-mentioned solutions, the shape of the shaped tire in step 1) is a cylindrical shape with a smooth surface (polymer filaments are directly deposited on the cylindrical surface), a cylindrical shape with grooves on the surface (polymer filaments are directly deposited on the cylindrical surface). The filaments are deposited in the grooves, and the cross-section of the grooves can be conical, circular or other shapes); preferably, the shaped mold is prepared by 3D printing technology or traditional technology such as CNC machining method.

In any of the above solutions, preferably, in step 4), a clamp is used to fix the mold, or the hollow shaped mold is sleeved on the rotating rod of the fourth axis system for fixing.

Preferably in any of the above-mentioned solutions, the fixation in step 4) is to replace the rotating rod of the fourth axis system with the shaped tire to receive the polymer, fix it on the fourth axis system, and make it possible. Forward or reverse rotation is performed under the control of the computer control system.

The size and geometry of the polymer fibers used to deposit the embolic device, the number of fibers per unit volume, and the structural pattern of the fibers are, in most cases, more controlled by certain aspects of the manufacturing equipment , such as controlled by a rotating rod, shaping tool or extrusion head.

The diameter of the shaped mold can be designed according to the unit size required by the embolization device. Generally, the diameter of the extruded polymer fiber is determined by the inner diameter of the extrusion head, the extrusion speed, and the movement of the extrusion head along the rotating rod. The speed and the rotational speed of the rotary lever are determined.

The embolic device of the present invention can be deployed interventionally at a desired location. First, it is compressed in the delivery sheath in the form of a silk chain, reaches the lesion, is pushed out, and spirals according to the original style to fill the lesion cavity.

In the present invention, the non-developing polymer provides physical properties. If the proportion is too low, it will affect the conveying and molding of the product. , the physical properties have been affected, and the physical preparation method has failed. If the proportion of the surfactant is too high, it will adhere to the surface of the product, cause interference to the product, adsorb particles, and also affect the performance of the product.

The preparation method of the present invention utilizes the four-axis rapid prototyping system in the patent applications CN102149859A and CN104274867A that have been published by the applicant. The extruded polymer fibers are deposited on the shaped tire or directly on the rotating rod according to the set speed, pattern and wire running mode. The preparation method of the embolization device of the present invention is simple, flexible and efficient.

The structure of the embolization device of the present invention is designed by a computer program; the size and geometry can be designed by a computer program, or controlled by a rapid prototyping system, or both can be controlled simultaneously.

The present invention prepares a polymer embolization device with a universal joint helix structure by using a polymer raw material and a four-axis rapid prototyping system. The polymer composite material of the present invention and the preparation method of the embolization device thereof have the following advantages:

1. Degradable polymers can be used, which can be degraded and absorbed naturally after use, which relieves the permanent threat of metal materials to patients, and can restore the natural physiological structure and function of the blood vessel wall.

2. The developing polymer increases the visibility, realizes the function of traceability during and after implantation, and simplifies the operation. Degradable//non-degradable polymers can be used. Compared with magnesium metal, the biocompatibility of the material is better, and the MRI examination of the patient is not affected.

3. Using the melt extrusion molding process, the material selection range is wide, and devices with different physical and chemical properties can be prepared, and compared with the existing spring coil preparation process (including welding, laser cutting and weaving technology), it is simple and efficient. , cost saving and more flexibility.

The perfect combination of design, material and process makes the prepared product not only can be curled into a group, but also can be supported and formed to overcome the scouring and compression of blood flow, and at the same time, it can quickly induce embolism and machine, so as to achieve better embolization effect.

In the present invention, the developer is incorporated into the polymer base material by the method of physical mixing, and the combination of the developer and the polymer material is promoted by adding a surfactant, so as to prepare a developable polymer with uniform mixing and good stability composite material. The preparation process does not need to use chemical solvents, so it will not cause environmental pollution and solvent residues, thereby making the materials prepared through the preparation method safer. And using four-axis rapid prototyping process, through special structural design, a developable polymer composite material-based embolization device has been developed, which has good imaging performance and embolization effect, and can be used for embolization treatment of hemangioma.

In the present invention, a fully degradable embolization device is integrally prepared through a four-axis rapid prototyping system, which is used for embolization treatment of vascular malformations. The perfect combination of design, material and process enables the prepared product to have better flexibility and packing formability, with a combination of rigidity and flexibility. It can not only adhere to the wall randomly, but also support forming, and overcome the erosion and compression of blood flow, so it can meet the needs of According to clinical needs, the implant can finally be completely degraded, releasing the confinement of the implant to the blood vessel and restoring the normal structural shape of the blood vessel. Moreover, the preparation method is simple and fast to operate, easy to change, low in cost, and suitable for industrialization.

The patented invention incorporates the developer into the polymer matrix material by physical mixing, and strengthens the combination of the developer and the polymer material by adding a surfactant, so as to prepare a developable polymer with uniform mixing and good stability composite material. In addition, the preparation process does not need to use chemical solvents, so environmental pollution and solvent residues are not caused, so that the materials prepared by the preparation method are safer. This patent uses a four-axis rapid prototyping system to integrate a polymer-based embolization device for the embolization treatment of vascular malformations. The combination of design, material and process makes the device have better flexibility and packing formability, which can meet different clinical needs. The implant can be completely degraded in the end, releasing the confinement of the implant on the blood vessels and restoring the blood vessels to normal. structural form. Moreover, the preparation method is simple and fast to operate, easy to change, low in cost, and suitable for industrialization.

Description of drawings

FIG. 1 is a schematic structural diagram of a preferred embodiment of a structure fabricated from a composite material according to the present invention.

FIG. 2 is a development effect diagram of the processed structure of the composite material shown in FIG. 1 .

FIG. 3 is a schematic structural diagram of another preferred embodiment of the processed structure of the composite material according to the present invention.

FIG. 4 is a development effect diagram of the processed structure of the composite material shown in FIG. 3 .

FIG. 5 is a schematic structural diagram of another preferred embodiment of the processed structure of the composite material according to the present invention.

FIG. 6 is a development effect diagram of the processed structure of the composite material shown in FIG. 5 .

FIG. 7 is a schematic view of the structure when the diameter of the wire of the spring coil is 0.35 mm.

FIG. 8 is the development effect of the structure shown in FIG. 7 .

FIG. 9 is a schematic view of the structure when the diameter of the wire of the spring coil is 0.45 mm.

Figure 10 shows the development effect of the structure shown in Figure 9 .

Fig. 11 is a schematic structural diagram of another preferred embodiment of the embolization device according to the present invention.

FIG. 12 is a development effect diagram of the structure shown in FIG. 11 .

Fig. 13 is a schematic structural diagram of another preferred embodiment of the embolization device according to the present invention.

FIG. 14 is a development effect diagram of the structure shown in FIG. 13 .

Fig. 15 is a schematic structural diagram of another preferred embodiment of the embolization device according to the present invention.

FIG. 16 is a development effect diagram of the structure shown in FIG. 15 .

Fig. 17 is a schematic structural diagram of another preferred embodiment of the embolization device according to the present invention.

FIG. 18 is a development effect diagram of the structure shown in FIG. 17 .

19 is a schematic structural diagram of the developing composite material when the developer in the developing composite material is 35%.

FIG. 20 is a development effect of the structure shown in FIG. 19 .

Figure 21 is a schematic structural diagram of the developing composite material when the developer in the developing composite material is 57%.

FIG. 22 is the development effect of the structure shown in FIG. 21 .

Figure 23 is a physical view of a preferred embodiment of a stent according to the present invention.

Figure 24 is a physical view of another preferred embodiment of the stent according to the present invention.

detailed description

In order to more correctly and clearly understand the content of the present utility model, further description and explanation are given below in conjunction with specific embodiments and accompanying drawings.

Example 1

The developing composite material, calculated in weight percentage, is made from the following raw materials: 45% non-developing high molecular polymer, 50% radiopacity modifier and 5% surfactant. Among them, the non-developing polymer is polycaprolactone (PCL), the radiopacity modifier is iopromide, and the surfactant is glycerin.

The preparation method of the developing composite material is as follows:

(1) according to the formula, take by weighing the preparation raw materials, blend, crush in a wall breaker, and stir evenly; wherein, the non-developing high molecular polymer can be particles, powders, and scraps;

(2) Melting and stirring: The melting and stirring device is shown in Figure 1. First, the raw materials are placed in a heating container to preheat, melt and stir, and the materials are fully mixed until the mixture can be pulled out of filaments. After granulation, it can be used for normal extrusion;

(3) Extrusion into filaments, the diameter of the filaments is 0.58±0.05mm, and the structure and development effect are shown in Figures 1 and 2.

The developing composites of this embodiment can be used to prepare embolic devices, such as spring coils.

The preparation method of the embolization device is as follows:

(i) preparing the developing composite material, which can be prepared in advance, or temporarily prepared according to the method, or purchase the developing composite material;

(ii) The composite material is prepared into a filament with a certain diameter (0.58±0.05mm) by melt extrusion into filament; then the obtained filament is wound and fixed at a predetermined diameter (such as 2mm, 3mm, 4mm) and length (such as 220mm) on the shaped tire, and then put the shaped tire and the wire into a heating device with a certain temperature (such as 40-50 ° C) for heat-setting. The heat-set shaped tire and the wire are taken out and cooled to room temperature, and the wire is removed from the shaped tire to obtain the desired developable device.

Alternatively, the preparation method of the embolization device is:

(ii) using a four-axis rapid prototyping system as a manufacturing facility, including the following steps:

4) adding the composite material of thermoplastic polymer, radiopaque modifier and surfactant into the distribution system of the four-axis rapid prototyping system;

5) According to the program designed in step 2), the XYZ positioning system and the fourth axis system are controlled by the computer control system, so that the distribution system can accurately extrude the polymer fibers according to the pre-designed deposition pattern of the polymer fibers, and deposit them on the fourth axis Specific locations of the rotatable shaped mouldings or directly deposited on the rotating rods to produce plug devices of specific size and structure;

6) Remove the plugging device prepared in step 5) from the shaped tire.

Wherein, the four-axis rapid prototyping system includes:

(i) the base;

In step 1), the shape of the shaped mold is a cylindrical shape with a smooth surface (the polymer filaments are directly deposited on the cylindrical surface), and a cylindrical shape with grooves on the surface (the polymer filaments are deposited in the grooves, the concave The cross section of the groove may be conical, circular or other shapes); preferably, the shaped tire is prepared by 3D printing technology or traditional technology such as CNC machining method.

In step 3), a clamp is used to fix the shaped tire, or the hollow mold is sleeved on the rotating rod of the fourth axis system for fixing.

The fixing in step 3) is to replace the rotating rod of the fourth axis system with the mold to receive the polymer, fix it on the fourth axis system, and make it can be forward or reverse under the control of the computer control system. Turn in the opposite direction.

The embolic device of the present invention can be deployed interventionally at a desired location. First, it is compressed in the delivery bridge in the form of a silk chain, reaches the lesion, and is pushed out, spiraling and filling the lesion cavity according to the original style.

The embolization device is used for embolization of blood vessels. In this embodiment, the embolization device can be used for embolization of intracranial aneurysms and other vascular malformations (eg, arteriovenous malformations and arteriovenous fistulas of the neurovasculature), as well as embolization of arteries and veins of the peripheral vasculature Treatment, in order to block the blood flow to the aneurysm or other vascular malformation, form a thrombus, and gradually organize, with the degradation of the material, the thrombus gradually shrinks and eventually disappears, and the vascular wall returns to normal shape and function.

The non-developing high molecular polymer can also be selected from polylactic acid (PLA), left-handed polylactic acid (PLLA), right-handed polylactic acid (PDLA), polyethylene glycol-polyglycolic acid (PGA), polycaprolactone ( PCL), polyethylene glycol (PEG), polyanhydride, polyhydroxyalkanoate (PHA), polydioxanone, polyiminocarbonate, polyfumaric acid, polycarbonate, polyurethane, polyphenylene A copolymer or mixture of one or more of olefins, polyolefins, and polychloroolefins. The surfactant is selected from one or more of the following: sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyethylene glycol tert-Octylphenyl ether, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), poly(propylene glycol)-block-poly(ethylene glycol)-block- Poly(propylene glycol) and other polyglycol-based polymers, polyoxyalkylenes.

Among them, for the four-axis forming system and forming method, reference is made to the four-axis rapid forming system and forming method in the patent applications CN102149859A and CN104274867A that have been published by the applicant, which will not be repeated here.

Example 2.1

Different from Example 1, the wire diameter is 0.7±0.05mm, and the structure and its developing effect are shown in Figures 3 and 4.

Example 2.2

The difference from Example 1 is that the wire diameter is 0.85±0.05mm, and the structure and its developing effect are shown in FIGS. 5 and 6 .

Example 2.3

Different from Example 1, the wire diameter (diameter) was 0.35±0.03 mm. The structure and its development effect are shown in Figures 7 and 8.

Example 2.4

Different from Example 1, the wire diameter (diameter) was 0.45±0.04 mm. The structure and its development effect are shown in Figures 9 and 10.

Example 2.5

Different from Example 1, the wire diameter (diameter) was 0.08±0.01 mm. The results show that the developing effect is good.

Example 2.6

Different from Example 1, the wire diameter (diameter) was 0.2±0.02 mm. The results show that the developing effect is good.

Example 2.7

Different from Example 1, the wire diameter (diameter) was 0.9±0.05 mm. The results show that the developing effect is good.

Example 3.1

Different from Example 1, the composition in the composite material is iopamidol 1:1 PCL. Figures 11 and 12 show the structure processed by the developing composite material of this embodiment and its developing effect.

Example 3.2

Different from Example 1, the composition of the composite material is bismuth subcarbonate 1:1 PCL. Figures 13 and 14 show the structure processed by the developing composite material of this embodiment and its developing effect.

Example 3.3

Different from Example 1, the composition of the composite material is 1:1 PCL of hydroxyapatite. Figures 15 and 16 show the structure processed by the developing composite material of this embodiment and its developing effect.

Example 3.4

Different from Example 1, the composition of the composite material is 1:2 PCL of hydroxyapatite. Figures 17 and 18 show the structure processed by the developing composite material of this embodiment and its developing effect.

Example 4.1

Different from Example 1, the radiopacity modifier in the composite material is calcium phosphate.

Example 4.2

Different from Example 1, the radiopacity modifier in the composite material is barium sulfate.

Example 4.3

Different from Example 1, the radiopacity modifier in the composite material is zirconium dioxide.

Example 4.4

Different from Example 1, the radiopacity modifier in the composite material is strontium halide.

Comparing Examples 1 and 3.1-3.3, it can be seen that: 1. The development of bismuth subcarbonate is better than that of iopamidol; 2. The extrusion of bismuth subcarbonate is better than that of iopamidol; 3. There is powder residue after the extrusion of bismuth subcarbonate + PCL , Iopamidol + PCL is good after sending; 4. Hydroxyapatite + PCL has poor development and is not easy to extrude.

Example 5

Different from Example 1, the developing composite material is made of the following raw materials in weight percent: non-developing high molecular polymer 45%, radiopacity modifier 52% and surfactant 3%. Among them, the non-developing high molecular polymer is polycaprolactone (PCL), the radiopacity modifier is bismuth subcarbonate, and the surfactant is silicone oil.

Example 6

Different from Example 1, the developing composite material is made of the following raw materials by weight percentage: 40% non-developing high molecular polymer, 55% radiopacity modifier and 5% surfactant. Among them, the non-developing high molecular polymer is polycaprolactone (PCL), the radiopacity modifier is bismuth subcarbonate, and the surfactant is glycerin.

Comparative Example 1

Different from Example 1, among the developing polymers used, the non-developing high molecular polymer was 26%, the developer (radio-opaque modifier) was used at 35%, and the surfactant was 39%. Figures 19 and 20 show the structure processed by the developing composite material of this embodiment and its developing effect.

Comparative Example 2

Different from Example 1, among the developing polymers used, the non-developing high molecular polymer was 17.2%, the developer (radio-opaque modifier) was used in an amount of 57%, and the surfactant was 25.8%. Figures 21 and 22 show the structure processed by the developing composite material of this embodiment and its developing effect.

Comparative Example 3

Different from Example 1, the impermeability modifier is calcium tungstate. The results show that the development effect is very poor, no development can be seen at all, and it is not easy to extrude.

Example 7

When preparing the developing composite material, different from Example 1, all the raw materials were dispersed in a solvent (such as chloroform, dichloromethane, dimethyl sulfoxide, etc.), and then the solution was magnetically stirred at room temperature until the solution After volatilization, it is extruded into filaments.

Example 8

Different from Embodiment 1, the stent of this embodiment is shown in FIG. 23 .

Example 9

The surface of the embolization device is covered with degradable/non-degradable macromolecules that can easily adsorb blood components to optimize delivery. Degradable/non-degradable polymer membranes can be loaded by dipping, spraying, or electrospinning. The degradable/non-degradable polymer film contains or does not contain drugs with high embolization effect. The surface of the embolization device may also not be covered with a degradable/non-degradable polymer film that easily absorbs blood components.

For example, the difference between this embodiment and embodiment 8 is that this embodiment provides a stent-graft, as shown in FIG. 24 , the covering is PLLA/PCL, which is realized by electrospinning, and the distance between the electrospinning equipment is adjusted, or The thickness and speed of the coating can be controlled by adjusting the size of the central metal rod.

The surface of the embolic device can also be wrapped with degradable polymer cilia to promote coagulation. It is also possible not to entangle the degradable polymer cilia.

The composite material of the present invention can also be used to prepare an embolization device, a vascular stent, a natural orifice stent, a thrombectomy device, a drug release device, a covered stent or an occluder, etc. The preparation method can refer to the preparation in the prior art method.

It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, but not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: it is still The technical solutions recorded in the foregoing embodiments may be modified, or some or all of the technical features thereof may be equivalently replaced; and these modifications or replacements do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention .

Claims

The developing composite material is made from the following raw materials by weight percentage: 20-80% of non-developing high molecular polymer, 80-20% of opacity modifier and 0-10% of surfactant.
The developing composite material according to claim 1, wherein the non-developing high molecular polymer is a thermoplastic polymer; preferably, the non-developing high molecular polymer is selected from polylactic acid (PLA), L-polylactic acid (PLLA) ), dextro-polylactic acid (PDLA), polyethylene glycol-polyglycolic acid (PGA), polycaprolactone (PCL), polyethylene glycol (PEG), polyanhydride, polyhydroxyalkanoate (PHA), One or more copolymers or mixtures of polydioxanone, polyiminocarbonate, polyfumaric acid, polycarbonate, polyurethane, polyphenylene olefin, polyolefin, and polychloroolefin; The radiopacity modifier is selected from one or more of the following: calcium phosphate, bismuth subcarbonate, iodine compounds used as contrast agents, barium sulfate, zirconium dioxide, strontium halide; preferably, the surfactant is selected from One or more of the following: sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyethylene glycol tert-octyl phenyl ether, Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), poly(propylene glycol)-block-poly(ethylene glycol)-block-poly(propylene glycol), etc. Alcohol polymers, polyoxyalkylenes.
The developing composite material according to claim 1, characterized in that, by weight percentage, the developing composite material is composed of: preferably, 20%-79.99% of non-developing high molecular polymer, 79.99% of impermeability modifier -20% and surfactant 0.01%-10%, or do not develop high molecular polymer 20%-79%, opacity modifier 79%-20% and surfactant 1%-5%, or do not develop high Molecular polymer 30%-70%, impermeability modifier 20%-69% and surfactant 1%-10%, or by weight percentage, the developing composite material is composed of: non-developing high molecular polymer 30 %-60%, impermeability modifier 30%-65% and surfactant 1%-5%, or the developing composite material is composed of: non-developing high molecular polymer 42%-45%, impermeability improvement 52%-55% of surfactant and 3%-5% of surfactant; preferably, the developing composite material is composed of: 45% of non-developing high molecular polymer, 50% of radiopacity modifier and 5% of surfactant, or The developing composite material is composed of 45% non-developing high molecular polymer, 52% radiopacity modifier and 3% surfactant.
The preparation method of the developing polymer described in any one of claim 1-3, step is as follows:

(1) Prepare raw materials according to the formula;

(2) Mix all the raw materials together, use conventional melt mixing methods, such as melt stirring, use a twin-screw or single-screw extruder, and perform melt mixing, extrusion or granulation, or the raw materials are dissolved in a solvent and mixed evenly, remove the solvent, extrusion or granulation to obtain the developing composite material;

Preferably, in step (2), the melting and stirring are placed in a heating container, and the temperature is heated to above the melting point of the high molecular polymer, and stirring is performed to melt and mix the materials uniformly.
Use of the developing polymer according to any one of claims 1 to 3 in the preparation of implantable and interventional medical devices, preferably the implantable medical device is of small size, preferably the implantable medical device is Embolization devices, coils, vascular stents, natural orifice stents, thrombectomy devices, drug release devices, covered stents or occluders.
An implantable and interventional medical device, prepared by using the developing composite material described in any one of claims 1-3 or obtained by the preparation method of claim 4, preferably the silk of the implantable and interventional medical device The diameter is 0.08-1mm; the surface of the implantable and interventional medical device is wrapped or not wrapped with degradable polymer cilia, and/or the surface of the implantable and interventional medical device is covered or not, and it is easy to absorb blood components The degradable/non-degradable polymer film, preferably the degradable/non-degradable polymer film can be covered by dipping or spraying or electrospinning; further preferably, the degradable/non-degradable polymer film contains or does not contain A drug with high embolization effect, the implantable and interventional medical device includes an embolization device, a coil, a vascular stent, a natural orifice stent, a thrombectomy device, a drug release device, a covered stent or an occluder.
The preparation method of the implanted, interventional medical device of claim 6, the steps are as follows:

(i) preparing the developing composite;

(ii) preparing the composite material into a filament with a certain diameter by using the method of melt extrusion into filament; then the obtained filament is wound and fixed on a shaped object with a certain size and shape according to a certain rule, and then the The shaped object and the filament are placed in a heating device with a certain temperature for heat-setting, the shaped object and the filament after heat-setting are taken out and then cooled to room temperature, and the desired developing device is obtained by removing the filament from the shaped object; or,

(iii) Using a four-axis rapid prototyping system as a manufacturing equipment, including the following steps:

1) according to the structure of the embolization device to be prepared, prepare the shaped mold;

2) A program for designing the deposition pattern of polymer fibers by computer;

3) Fixing the shaped mold to the position of the rotating rod of the fourth axis system of the four-axis rapid prototyping system, so that it can be forward or reverse with the fourth axis rotating rod under the control of the computer control system. reverse rotation;

4) adding the composite material of the thermoplastic polymer prepared above, the radiopaque modifier and the surfactant into the distribution system of the four-axis rapid prototyping system;

5) According to the program designed in step 2), the XYZ positioning system and the fourth axis system are controlled by the computer control system, so that the distribution system can accurately extrude the polymer fibers according to the pre-designed deposition pattern of the polymer fibers, and deposit them on the fourth axis The specific location of the rotatable shaped tire or directly deposited on the rotating rod, thereby producing the plug device of specific size and structure;

6) remove the embolization device prepared in step 5) from the shaped tire;

Wherein, the four-axis rapid prototyping system preferably includes:

(i) the base;

(ii) a three-axis X-Y-Z positioning system attached to the base, wherein the X-Y-Z positioning system defines the X, Y, Z directions, respectively;

(iii) a dispensing system mounted on and moved by said X-Y-Z positioning system, said dispensing system containing an extrusion head;

(iv) a fourth axis system connected to the base, comprising a rotating rod connected to the base below the extrusion head, wherein the rotating rod can be forward or reversed about its axis rotate; the central axis of the rotating rod is parallel to the Y axis; and

(v) A computer control system, which can precisely control the XYZ positioning system according to the set program to precisely control the movement of the extrusion head of the distribution system in the X, Y, Z directions, and precisely control the fourth axis system. The rotation of the rotating rod about its axis.
The preparation method according to claim 7, characterized in that, in step 1), the shape of the shaped tire is a cylindrical shape with a smooth surface and a cylindrical shape with grooves on the surface; preferably, the shaped tire has a cylindrical shape. It is prepared by 3D printing technology or traditional technology such as CNC machining method.
The preparation method according to claim 8, characterized in that, in step 4), a clamp is used to fix the shaped tire, or the hollow shaped tire is fixed on the rotating rod of the fourth shaft system.
The preparation method according to claim 9, wherein the fixing in step 4) is to replace the rotating rod of the fourth shaft system with the shaped tire to receive the polymer, and fix it on the fourth shaft system , and enable it to rotate forward or reverse under the control of the computer control system.