CN111849136A

CN111849136A - Full-biological absorbable composite material, application, intravascular stent and preparation method thereof

Info

Publication number: CN111849136A
Application number: CN202010724016.2A
Authority: CN
Inventors: 郑柳春
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-06-28
Filing date: 2020-07-24
Publication date: 2020-10-30

Abstract

The invention discloses a fully-bioabsorbable composite material, which comprises: fully bioabsorbable polymers, and bio-based nanocrystals. In addition, the invention also discloses the application of the fully-bioabsorbable composite material, which is used for manufacturing the vascular stent. Secondly, the invention also discloses a preparation method of the full-biological absorbable composite material, which comprises the following steps: the bioabsorbable polymer and the bio-based nanocrystals are blended. Furthermore, the invention also discloses a preparation method of the intravascular stent, which comprises the following steps: preparing the vascular stent: extruding the full-biological absorbable composite material through a melting die to obtain the vascular stent; surface modification: and carrying out surface modification on the vascular stent. Finally, the invention also discloses a vascular stent which is prepared by the preparation method. When the bioabsorbable composite material is applied to the vascular stent, the obtained vascular stent has the advantages of good mechanical property, good biocompatibility and good biodegradability.

Description

Full-biological absorbable composite material, application, intravascular stent and preparation method thereof

Technical Field

The invention belongs to the field of biological materials, and particularly relates to a biological material for a vascular stent, application, a preparation method, the vascular stent and a preparation method thereof. In particular to a high-performance total biological absorption blood vessel stent and a preparation method thereof.

Background

With the change of life style and dietary structure, cardiovascular and cerebrovascular diseases have become major diseases threatening the health of people gradually. The implantation of vascular stents is also becoming more common and has become the most effective means for treating cardiovascular and cerebrovascular diseases.

The metal stent material such as stainless steel, NiTi alloy, cobalt-chromium alloy and the like becomes an important preparation material of the traditional vascular stent due to good biocompatibility and radial supporting force. However, these metal stent materials do not have biodegradability, so there are problems that late thrombosis and in-stent restenosis are caused after long-term retention in vivo after implantation, and patients need to take anticoagulant drugs for a long time.

Therefore, research focuses on a completely absorbable vascular stent material to effectively solve the problems of related complications caused by poor matching of traditional non-degradable metals and human tissues and long-term stent residue.

The completely absorbable blood vessel stent material mainly comprises iron alloy, magnesium alloy and degradable polymer material. Among them, the vascular stent material using iron alloy and magnesium alloy has defects, such as: the corrosion rate is slow, the corrosion products block blood vessels, and the degradation rate is uncontrollable, which easily causes the accumulation of metal ions.

However, although degradable polymer materials have the advantages of adjustable degradation rate and no toxic side effects of degradation products, they have disadvantages such as large thickness, large brittleness and insufficient radial support strength.

Through the search of documents and patents, patents and documents related to biocomposites are, for example: chinese patent document No. CN109880180A, published as 2019, 6, month, and 14 entitled "nanocellulose/cellulose composite, reinforced polylactic acid 3D printing material, and preparation method thereof" discloses a nanocellulose/cellulose composite and related reinforced 3D printing material that can be used for polylactic acid 3D printing material. In the technical solution disclosed in this patent document, since a large amount of acid and silane coupling agent, plasticizer, and heat stabilizer are used, biocompatibility is poor, and it cannot be used for preparing vascular stents.

Another example is: chinese patent publication No. CN109453437A, published as 3/12/2019, entitled "a nanofiber-reinforced absorbable vascular stent and a preparation method thereof", discloses a nanofiber-reinforced absorbable vascular stent. However, the technical solution disclosed in this patent document does not relate to the enhancement of the supporting strength.

Based on the above, it is desirable to obtain a bioabsorbable composite material, which can overcome the defects of the prior art, and when the bioabsorbable composite material is applied to a vascular stent, the obtained vascular stent has the advantages of good mechanical properties, good biocompatibility and good biodegradability.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to provide a fully-bioabsorbable composite material, application, a vascular stent and a preparation method thereof.

In order to achieve the above object, the present invention proposes a fully bioabsorbable composite comprising a fully bioabsorbable polymer and bio-based nanocrystals.

Preferably, in the fully bioabsorbable composite material of the present invention, the mass percentage of the fully bioabsorbable polymer in the fully bioabsorbable composite material is 70-98%.

Preferably, in the fully bioabsorbable composite material, the mass percentage of the bio-based nanocrystals in the fully bioabsorbable composite material is 2-30%.

In the fully bioabsorbable composite material of the present invention, the fully bioabsorbable polymer is used because it has good biocompatibility and can be completely degraded in vivo.

The bio-based nanocrystals are used because: the bio-based nanocrystals and the fully bio-absorbable polymer form a nano composite material, and can simultaneously realize toughening and reinforcement of a high molecular material.

The mass percentage range of the bio-based nanocrystals is set to 2-30% because: when the mass percent of the bio-based nanocrystals is less than 2%, the bio-based nanocrystals cannot play an obvious role in enhancing and toughening, and when the mass percent of the bio-based nanocrystals is 30%, the mechanical property of the composite material is improved to the highest value.

More preferably, the total bioabsorbable polymer in the total bioabsorbable composite material is 70-90% by mass, and the bio-based nanocrystals are 10-30% by mass.

In addition, it should be noted that, in the technical solution of the present invention, for the fully bioabsorbable composite material, the adopted bio-based nanocrystals not only have a nano effect, but also can be used as physical cross-linking points to uniformly distribute stress in polymerization, thereby simultaneously realizing toughening and reinforcement of the fully bioabsorbable polymer.

Preferably, in the fully bioabsorbable composite material of the present invention, the fully bioabsorbable polymer includes one or more of poly (L-lactic acid), poly (glycolic acid), poly (lactic-co-glycolic acid), poly (dioxanone), poly (caprolactone), poly (hydroxy fatty acid ester), poly (acrylate), poly (succinate), poly (beta-hydroxybutyrate valerate), poly (ethylene adipate), and poly (butylene succinate).

Preferably, in the fully bioabsorbable composite material of the present invention, the bio-based nanocrystals include one or more of cellulose nanocrystals, starch nanocrystals, chitosan nanocrystals, and poly-l-lactic acid nanocrystals.

Accordingly, in order to achieve the above object, the present invention also proposes the use of the above-mentioned fully bioabsorbable composite material for the manufacture of vascular stents.

In addition, in order to achieve the above object, the present invention further provides a method for preparing the above fully bioabsorbable composite material, comprising the steps of: the bioabsorbable polymer and the bio-based nanocrystals are blended.

Preferably, in the preparation method, the blending temperature is 90-320 ℃, the rotating speed is 5-500 rpm, and the blending time is 1-30 min.

In the above scheme, the blending temperature needs to be set according to the melting point of the adopted polymer, which is generally 20 to 60 ℃ higher than the melting point of the adopted polymer, for example, the melting point of polycaprolactone is 60 ℃, and therefore, the blending temperature can be set to 80 to 120 ℃.

Furthermore, in order to achieve the above object, the present invention further provides a method for preparing a vascular stent, comprising the steps of:

preparing the vascular stent: and extruding the completely-bioabsorbable composite material through a melting die to obtain the vascular stent.

In some embodiments, the vascular stent may be surface modified, for example by laser surface modification to remove a thin layer in the vascular stent.

It should be noted that, when extruded by the melting die, the vascular stent formed by the total bioabsorbable composite material is in a net-shaped framework structure, and the whole net-shaped framework is formed by cross-linking filaments formed by extruding the total bioabsorbable composite material, and the filaments are linked with each other through thin layers, that is, the thin layers are positioned between the filaments of the net-shaped framework of the vascular stent.

In addition, in some embodiments, the vascular stent may also be drug coated. The solution adopted for coating the medicine can be an active medicine solution, the active medicine solution comprises degradable polymers and active medicines, wherein the degradable polymers comprise one or more of poly-L-lactic acid, polyglycolic acid, poly-lactic-glycolic acid, polydioxanone, polycaprolactone, polyhydroxyalkanoate, polyacrylate, polybutylene succinate, poly (beta-hydroxybutyrate), poly (beta-hydroxybutyrate valerate), polyethylene glycol adipate and polybutylene succinate. The active medicine comprises one or more of antioxidant medicine, anticoagulant medicine, anticancer medicine, medicine for inhibiting vascular smooth muscle cell proliferation, anti-inflammatory medicine or immunosuppressant medicine. The active agent may be, for example: one or more of rapamycin, tacrolimus, everolimus, paclitaxel, cilostazol, triptolide, or dexamethasone.

In order to achieve the purpose, the invention also provides a vascular stent which is prepared by the preparation method.

Compared with the prior art, the fully-bioabsorbable composite material, the application, the intravascular stent and the preparation method thereof have the following beneficial effects:

1. the completely-bioabsorbable material provided by the invention has the technical characteristics of completely-bioabsorbable polymer and bio-based nanocrystalline, so that the final completely-bioabsorbable material has good mechanical property, good biocompatibility and excellent biodegradability.

2. The preparation method of the fully-bioabsorbable material is simple, easy for industrial production and not harsh in production conditions.

3. The vascular stent prepared from the fully-bioabsorbable material has high radial supporting force and good biocompatibility.

4. In some embodiments, the intravascular stent has the anticoagulant function, the angiogenesis function and the biodegradation function because the intravascular stent is coated with the drugs, so that a patient does not need to take the anticoagulant drugs externally during the use process.

Detailed Description

The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that it would be obvious to those skilled in the art that various changes and modifications can be made without departing from the spirit of the invention. All falling within the scope of the present invention.

The blending apparatus used in the examples and comparative examples of the present invention was a reactive twin screw extruder, which may be the hake Polylab OS system of seimer feishell technologies ltd.

The melt mold extrusion used was a small injection molding machine (type Haake Minijet, Germany) with a mold temperature of 30-150 ℃.

The worthwhile radial strength was measured on an MSI tester (model numbers Machines Solutions inc., Flagstaff, AZ).

Cytotoxicity test: endothelial cells are used for testing, and the cytotoxicity test result is used for representing the biocompatibility of the vascular stent.

Biodegradation Performance test experiments: firstly, washing a blood vessel stent sample with deionized water, fully drying the blood vessel stent sample in a vacuum drying oven at 40 ℃, placing the dried sample in a culture dish containing Phosphate Buffer Solution (PBS) with the pH value of 7.2, then moving the culture dish in which the blood vessel stent sample is placed into the culture oven at 37 ℃, wherein the degradation time lasts for 50 weeks, replacing the culture solution once per week, taking out the sample every 2 weeks, soaking and washing the sample in the deionized water for 3 times, then sucking water on the surface by using filter paper, placing the sample in the vacuum drying oven at 40 ℃ for drying for 6 hours, then taking out the sample for testing, and after testing, placing the sample back into the culture solution for continuous degradation for subsequent testing.

Example 1

Drying polyhydroxy butyric acid at 100 ℃ for 12 hours in advance, weighing 300g of polyhydroxy butyric acid and cellulose nanocrystal, wherein the mass percent of polyhydroxy butyric acid in the total is 95 wt%, the mass percent of cellulose nanocrystal in the total is 5 wt%, mixing the components uniformly, and adding the mixture into a double-screw extruder for mixing, extruding and granulating.

The parameters of the twin-screw extruder were set as follows:

drying granules obtained by mixing and blending a double-screw extruder at 100 ℃ for 12h, placing the granules in a small injection molding instrument, heating to 235 ℃ for melting, wherein the pressure of an extrusion head is 8MPa, heating the granules obtained by mixing to a molten state, extruding the granules in the molten state into a molten die for extrusion, and extruding to obtain the vascular stent with the outer diameter of 5mm and the wall thickness of 0.3 mm.

Dissolving polylactic acid and paclitaxel (95 parts by mass of polylactic acid: 5 parts by mass of paclitaxel) in chloroform solution (10 wt%) to obtain a pharmaceutically active solution, spraying the pharmaceutically active solution on the surface of the intravascular stent, and drying the sprayed stent at room temperature to obtain the final intravascular stent. The radial strength of the vascular stent is 900KPa, the thickness is 0.32mm, the endothelial cells are cultured for 24 hours, the survival rate is 98 percent, and the biodegradable quantity is 64 percent in 50 weeks. Therefore, the intravascular stent in the embodiment 1 has good mechanical property, good biocompatibility and good biodegradability.

Example 2

Drying poly-L-lactic acid at 100 ℃ for 12h in advance, weighing 300g of poly-hydroxybutyrate and starch nanocrystal, wherein the poly-L-lactic acid accounts for 70 wt% of the total mass, the starch nanocrystal accounts for 30 wt% of the total mass, uniformly mixing the components, and adding the mixture into a double-screw extruder for mixing, extruding and granulating. The parameters of the twin-screw extruder were set as follows:

drying granules obtained by mixing and blending a double-screw extruder at 100 ℃ for 12h, placing the dried granules in a small injection molding machine, heating to 195 ℃ for melting, wherein the pressure of an extrusion head is 6MPa, heating the mixed granules to a molten state, extruding the molten granules into a molten die for extrusion, and extruding to obtain the vascular stent with the outer diameter of 7mm and the wall thickness of 0.2 mm.

The method comprises the steps of dissolving polylactic acid and everolimus (90 parts by weight of polylactic acid: 10 parts by weight of everolimus) in chloroform solution (6 wt%) to obtain a medicinal active solution, spraying the medicinal active solution on the surface of the intravascular stent, and drying the sprayed stent at room temperature to obtain the final intravascular stent. The radial strength of the intravascular stent is 360KPa, the thickness is 0.31mm, the endothelial cells are cultured for 24 hours, the survival rate is 99 percent, and the biodegradable quantity is 61 percent in 50 weeks. Therefore, the intravascular stent in the embodiment 2 has good mechanical property, good biocompatibility and good biodegradability.

Example 3

Drying polycaprolactone at 40 ℃ for 12 hours in advance, weighing 300g of polycaprolactone and chitosan nanocrystal, wherein the polycaprolactone accounts for 80 wt% of the total mass, the starch nanocrystal accounts for 20 wt% of the total mass, mixing the components uniformly, adding the mixture into a double-screw extruder, and mixing, extruding and granulating. The parameters of the twin-screw extruder were set as follows:

the parameters of the twin-screw extruder were set as follows:

drying granules obtained by mixing and blending a double-screw extruder at 40 ℃ for 12h, placing the dried granules in a small injection molding machine, heating to 90 ℃ for melting, wherein the pressure of an extrusion head is 1MPa, heating the mixed granules to a molten state, extruding the molten granules into a molten die for extrusion, and extruding to obtain the vascular stent with the outer diameter of 20mm and the wall thickness of 0.3 mm.

Dissolving polylactic acid and paclitaxel (5 parts by weight of polylactic acid: 95 parts by weight of paclitaxel) in chloroform solution (3 wt%) to obtain pharmaceutically active solution, and applying the pharmaceutically active solution to the surface of the blood vessel stent at a ratio of 100ug/cm²The spraying mode is adopted for spraying, and the sprayed stent is dried at room temperature to obtain the intravascular stent. The radial strength of the vascular stent is 80KPa, the thickness is 0.36mm, and endothelium is thinnedAfter cell culture for 24h, the survival rate is 97 percent, and the biodegradable quantity is 76 percent in 50 weeks. Therefore, the intravascular stent in the embodiment 3 has good mechanical property, good biocompatibility and good biodegradability.

Example 4

Drying a polyhydroxybutyrate-valerate copolymer (with the content of 20mol of butyric acid) at 100 ℃ for 12 hours in advance, weighing 300g of the polyhydroxybutyrate-valerate copolymer and starch nanocrystals, 85 wt% of the polyhydroxybutyrate-valerate copolymer and 15 wt% of polylactic acid nanocrystals, uniformly mixing the components, and adding the mixture into a double-screw extruder for mixing, extruding and granulating. The parameters of the twin-screw extruder were set as follows:

the parameters of the twin-screw extruder were set as follows:

drying the pellets obtained by blending at 100 ℃ for 12h, placing the pellets in a small injection molding machine, heating the pellets to 235 ℃ for melting, heating the mixed pellets to a molten state under the pressure of an extrusion head of 12MPa, extruding the molten pellets into a melting mold for extrusion to obtain the stent with the outer diameter of 3mm and the wall thickness of 0.2 mm.

Polycaprolactone and rapamycin (60 parts by mass of polycaprolactone: 40 parts by mass of rapamycin) are dissolved in a chloroform solution (5 wt%) to obtain a pharmaceutically active solution, the pharmaceutically active solution is sprayed on the surface of the intravascular stent, and the sprayed stent is dried at room temperature to obtain the intravascular stent. The radial strength of the vascular stent is 900KPa, the thickness is 0.38mm, the endothelial cells are cultured for 24 hours, the survival rate is 99 percent, and the biodegradable quantity is 68 percent in 50 weeks. Therefore, the intravascular stent in the embodiment 4 has good mechanical property, good biocompatibility and good biodegradability.

Comparative example 1

Comparative example 1 a vascular stent was fabricated by the same fabrication process as in example 1, except that cellulose nanocrystals were not mixed into the pellets of comparative example 1. The radial strength of the finally obtained vascular stent is 600KPa, the thickness is 0.32mm, the endothelial cells are cultured for 24 hours, the survival rate is 93 percent, and the biodegradable quantity is 61 percent in 50 weeks.

As can be seen from the combination of comparative example 1 and example 1, comparative example 1 cannot form a nanocomposite with a fully bioabsorbable polymer because comparative example 1 does not employ bio-based nanocrystals, and thus comparative example 1 cannot simultaneously achieve toughening and reinforcement of a high molecular material, and thus the radial strength of the vascular stent of comparative example 1 is inferior to that of example 1.

It should be noted that the prior art in the protection scope of the present invention is not limited to the examples given in the present application, and all the prior art which is not inconsistent with the technical scheme of the present invention, including but not limited to the prior patent documents, the prior publications and the like, can be included in the protection scope of the present invention.

In addition, the combination of the features in the present application is not limited to the combination described in the claims of the present application or the combination described in the embodiments, and all the features described in the present application may be freely combined or combined in any manner unless contradictory to each other.

The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes or modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention. The embodiments and features of the embodiments of the present application may be combined with each other arbitrarily without conflict.

Claims

1. A fully bioabsorbable composite, characterized in that it comprises: fully bioabsorbable polymers, and bio-based nanocrystals.

2. The fully bioabsorbable composite of claim 1, wherein the percentage by mass of fully bioabsorbable polymer in the fully bioabsorbable composite is 70-98%.

3. The fully bioabsorbable composite of claim 1, wherein the mass percent of bio-based nanocrystals in the fully bioabsorbable composite is 2-30%.

4. The fully bioabsorbable composite of claim 1, wherein the fully bioabsorbable polymer comprises one or more of poly (L-lactic acid), poly (glycolic acid), poly (lactic-co-glycolic acid), poly (dioxanone), polycaprolactone, polyhydroxyalkanoate, polyacrylate, polybutylene succinate, poly (beta-hydroxybutyrate), poly (beta-hydroxybutyrate valerate), polyethylene adipate, polybutylene succinate.

5. The fully bioabsorbable composite of claim 1, wherein the bio-based nanocrystals comprise one or more of cellulose nanocrystals, starch nanocrystals, chitosan nanocrystals, poly-L-lactic acid nanocrystals.

6. Use of a fully bioabsorbable composite according to any of claims 1-5, for the manufacture of vascular stents.

7. A process for the preparation of a fully bioabsorbable composite according to any of claims 1-5, characterized in that it comprises the steps of: the bioabsorbable polymer and the bio-based nanocrystals are blended.

8. The preparation method according to claim 7, wherein the blending temperature is 90-320 ℃, the rotation speed is 5-500 rpm, and the blending time is 1-30 min.

9. A preparation method of a blood vessel stent is characterized by comprising the following steps:

preparing the vascular stent: extruding the fully bioabsorbable composite of any of claims 1-5 through a melt die to obtain the vascular stent.

10. A vascular stent prepared by the preparation method of claim 9.