CN102228721A - Degradable coronary stent and manufacturing method thereof - Google Patents
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- 238000012827 research and development Methods 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
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- Materials For Medical Uses (AREA)
Abstract
本发明提供了一种可降解冠脉支架，该冠脉支架以铁基材料为基体，且基体表面覆盖一层可降解高分子涂层；其中，所述可降解高分子涂层成分中含有酯键（-COO-）；具体的制备方法为将含有酯键的高分子材料溶于有机溶剂中，然后，采用浸涂或喷涂方法将其涂覆于铁基合金基体表面，且涂层厚度为1-40μm；该可降解冠脉支架不仅增大了铁基冠脉支架的降解/腐蚀速度，而且还提高了铁基合金的生物相容性，有利于内皮细胞在支架表面的快速内皮化，与此同时，该支架的制备方法简单，操作方便。The invention provides a degradable coronary stent, the coronary stent uses an iron-based material as a base, and the surface of the base is covered with a layer of degradable polymer coating; wherein, the degradable polymer coating contains ester bond (-COO-); the specific preparation method is to dissolve the polymer material containing ester bonds in an organic solvent, and then apply it to the surface of the iron-based alloy substrate by dipping or spraying, and the coating thickness is 1-40μm; the degradable coronary stent not only increases the degradation/corrosion rate of the iron-based coronary stent, but also improves the biocompatibility of the iron-based alloy, which is conducive to the rapid endothelialization of endothelial cells on the surface of the stent, At the same time, the preparation method of the scaffold is simple and the operation is convenient.
Description
Technical field
The present invention relates to technical field of biological materials, relate in particular to the coronary artery bracket field of coronary heart disease interventional therapy, a kind of degradable coronary artery bracket and preparation method thereof is provided especially.
Background technology
In recent years, interventional therapy has become the main flow treatment means of coronary heart disease, and implanting coronary artery bracket is the important component part of interventional therapy.What use clinically at present mainly is permanent stents, and the material of permanent stents mainly is nondegradable 316L rustless steel and Co-Cr alloy.Though permanent stents has solved acute closed, the at a specified future date thrombosis problem of the postoperative blood vessel of percutaneous coronary endoluminal vascular plasty (PTCA), but support has brought problems such as subacute stent thrombosis and in-stent restenosis after implanting thereupon, and the needs of patients of implant frame is taken the medicine of anti-platelet aggregation for a long time.For solving the in-stent restenosis problem, bracket for eluting medicament begins to be widely used in clinical treatment.Yet clinical research finds that bracket for eluting medicament is because the long-term existence of non-degradable metal rack to the long-time stimulus of peripheral vessels tissue, makes myocardial infarction and advanced thrombus incidence rate raise.The research and development of degradable coronary artery bracket are expected to solve above-mentioned problems.
The degradable coronary artery bracket should be able to retentivity be learned the integrity of performance in can 12 months after implantation, and the ferrum of progressively degrading fully again after blood vessel is finished reconstruction.At present, the investigation of materials of degradable coronary artery bracket mainly concentrates on and is divided into macromolecular material, magnesium alloy and ferrous alloy.The mechanical property performance of macromolecular material also far can not reach present clinical mechanical property level with coronary artery bracket; Magnesium alloy not only degradation speed is too fast, can't satisfy the requirement to the coronary artery bracket degradation speed, and its plasticity is relatively poor, is difficult to satisfy the requirement of large scale coronary artery bracket to plasticity.Ferrous alloy is comparatively active under the body fluid environment, has lower electrode potential, easily corrodes in the environment in vivo, thereby realizes degraded in vivo.Ferrous alloy is subjected to people's attention gradually with its good mechanical performance, biocompatibility and degradable in vivo performance, is expected to become degradable coronary artery bracket material of new generation.Ferrous alloy can further improve the mechanical property of alloy by alloying, satisfy the mechanical property requirements of coronary artery bracket, and ferrous alloy is opaque to X ray, makes things convenient for the observation in the implantation process, the part ferrous alloy is nonmagnetic, has good MRI compatibility.
Ferrous alloy starts from the beginning of this century as the research of degradable coronary artery bracket material, even will be early than the research of magnesium alloy coronary artery bracket.Calendar year 2001, Peuster etc. attempt as degradable coronary artery bracket material pure iron the earliest.Afterwards, the medical worker has proceeded a series of zoopery, shows that pure iron is reliable as degradable coronary artery bracket material safety, laboratory animal is not produced obvious toxic-side effects.
With respect to other degradable coronary artery bracket material, ferrous alloy has than remarkable advantages.But because at present ferrous alloy degradation speed in vivo is relatively slow, also can't satisfy clinically, therefore hinder the clinical practice of iron-based degradable coronary artery bracket the degradation time requirement of degradable coronary artery bracket.
In order to improve the degradation speed of iron-based degradable coronary artery bracket, material supplier author has carried out a series of research work, and wherein the ferrous alloy of the low corrosion potential of exploitation is trial the earliest, and the Fe-Mn series alloy of developing with people such as Hermanwan is main representative.After this, having occurred adding precious metal element in succession and formed intermetallic compound to increase galvanic corrosion tendency, preparation ultra-fine grain alloy with the new approaches that improve the ferrous alloy degradation speed etc., serve as mainly to represent with the ultra-fine grain pure iron of people such as the Fe-Mn-Pd alloy of people such as Schinhammer exploitation, Moravej by the electrochemical deposition preparation respectively.But from present experimental result, the degradation speed of new alloy in simulated body fluid do not have substantial raising with respect to pure iron, still can not satisfy the requirement of intravascular stent to material degradation speed.Owing to be accompanied by two processes of oxygen uptake corrosion and liberation of hydrogen corrosion in the ferrous alloy degradation process, and for the ferrous alloy in particular solution, its the highest oxygen uptake corrosion rate is a definite value, thereby by increasing very difficult realization of approach that the oxygen uptake corrosion rate improves the ferrous alloy degradation speed.
Summary of the invention
The object of the present invention is to provide a kind of degradable coronary artery bracket and preparation method thereof, the method of the liberation of hydrogen corrosion rate by improving ferrous alloy improves the corrosion rate of ferrous alloy in the Human Physiology environment, thereby realize improving the purpose of the degradation speed of ferrous alloy in physiological environment, its specific implementation method is: in ferrous alloy surface preparation degradable macromolecule coating, improve the liberation of hydrogen corrosion rate of ferrous alloy by the acidic micro-environment of this polymeric coating layer degraded generation.
A kind of degradable coronary artery bracket provided by the invention is characterized in that: this coronary artery bracket is matrix with the iron, and matrix surface covers one deck degradable macromolecule coating;
Wherein, contain ester bond (COO-) in the described degradable macromolecule coating material.
Described iron is a pure iron, Fe-Mn, Fe-Mn-C, Fe-Mn-S, Fe-Mn-Pt alloy system and other biodegradable ferrous alloy; The described material that contains ester bond is one or more in polylactic acid (PLA), polycaprolactone (PCL), polylactic acid-glycolic guanidine-acetic acid copolymer (PLGA), polyhydroxyalkanoate (PHA) or the polyacrylate (PEA).
Degradable coronary artery bracket provided by the invention, preferably at the inner curative drug that adds of polymeric coating layer, or for improving weight percentage that coating mechanical property, biology performance add less than 20% additive; Wherein, the concrete composition of additive is one or both in polycaprolactone (PCL) or the Polyethylene Glycol (PEG).
Degradable coronary artery bracket provided by the invention, the matrix of coronary artery bracket wherein and existing coronary artery bracket matrix are in full accord, we pass through in ferrous alloy surface coverage one deck degradable macromolecule coating, this polymeric coating layer is degraded in physiological environment, wherein the ester bond degraded produces and has tart carboxylic group, make the pH value of local microenvironment descend, thereby can improve the liberation of hydrogen corrosion rate of ferrous alloy, increase the corrosion/degradation speed of ferrous alloy in the Human Physiology environment.
The present invention also provides a kind of preparation method of degradable coronary artery bracket, it is characterized in that: concrete preparation process is as follows:
---the macromolecular material that will contain ester bond is dissolved in the organic solvent, and concentration range is 0.5-5w/v%, then, adopts dip-coating or spraying method that it is coated on the ferrous alloy matrix surface, and coating layer thickness is 1-40 μ m, dry getting final product in air or vacuum.
The preparation method of degradable coronary artery bracket provided by the invention, be different from design degradation speed ferrous alloy faster, the present invention produces by the degradable macromolecule coating degraded back that has ester bond has tart carboxylic group, near the pH value of the microenvironment of matrix is descended, thereby reduce the overpotential of ferrous alloy matrix surface evolving hydrogen reaction, make the easier generation of evolving hydrogen reaction, and then improve the degradation speed of matrix.The research and development that utilize the perishable performance of ferrous alloy to prepare the biodegradable ferrous alloy are just to begin in recent years to carry out.Though ferrous alloy is long at the engineering applicating history, yet its perishable performance is the unfavorable factor in the engineering application, and how ferrous alloy being protected is one of main task during engineering is used.And the acidic micro-environment that adopts the degraded of degradable macromolecule coating to form among the present invention improves the liberation of hydrogen corrosion rate of ferrous alloy, thereby increases the degraded/corrosion rate of iron-based coronary artery bracket, to satisfy the requirement of degradable coronary artery bracket to degradation speed.
Meanwhile, this degradable macromolecule coating also can further improve the biocompatibility of ferrous alloy, especially can reduce support the degraded initial stage toxic reaction, help the quick endothelialization of endotheliocyte at rack surface.In addition, this coating also has the medicine carrying function, can discharge curative drug in degradation process, suppresses the neointimal hyperplasia after support is implanted, and reduces the incidence rate of restenosis in the blood vessel.
Degradable coronary artery bracket provided by the invention and preparation method thereof, its advantage is: this degradable coronary artery bracket has not only increased the degraded/corrosion rate of iron-based coronary artery bracket, but also improved the biocompatibility of ferrous alloy, help the quick endothelialization of endotheliocyte at rack surface, meanwhile, the preparation method of this support is simple, and is easy to operate.
The specific embodiment
Further explain the present invention with specific embodiment below, but it does not limit the present invention.
Embodiment 1
At first, by weight proportion for 85:15, molecular weight are that 100,000 PLGA is dissolved in the ethyl acetate, concentration is 1w/v%, goes out the PLGA coating by spraying process in the pure iron surface preparation then with lactic acid and hydroxyacetic acid, thickness was 23.4 μ m, air drying 24 hours.
Apply the pure iron sample of PLGA coating, soak after 28 days in the 37oC normal saline, measuring its degradation rate by weight-loss method is 0.0405mm/year, is 4 times of no coating pure iron sample degradation speed.
Embodiment 2
At first, be that 80,000 PLA is dissolved in the acetone with molecular weight, concentration is 5w/v%, prepares the PLA coating by spraying process at the Fe-30Mn alloy surface then, thickness is 13.7 μ m.Air drying 12 hours.
Apply the Fe-30Mn alloy sample of PLA coating, soak after 28 days in the 37oC normal saline, measuring its degradation rate by weight-loss method is 0.0384mm/year, is 3.8 times of no coating Fe-30Mn alloy sample degradation speed.
Embodiment 3
At first, by weight proportion for 60:40, molecular weight are that 70,000 PLGA is dissolved in the chloroform, concentration is 5w/v%, prepares the PLGA coating by dip coating at the Fe-30Mn-1C alloy surface then with lactic acid and hydroxyacetic acid, thickness is 21.9 μ m, dry 12 hours in a vacuum.
Apply the Fe-30Mn-1C alloy sample of PLGA coating, soak after 28 days in the 37oC normal saline, measuring its degradation rate by weight-loss method is 0.0334mm/year, is 3.3 times of no coating Fe-30Mn-1C alloy sample degradation speed.
Embodiment 4
At first, by weight proportion for 50:50, molecular weight are that 100,000 PLGA is dissolved in the dichloromethane, concentration is 4w/v%, prepares the PLGA coating by dip coating at the Fe-30Mn-1S alloy surface then with lactic acid and hydroxyacetic acid, and thickness is 16.2 μ m.Dry 8 hours in a vacuum.
Apply the Fe-30Mn-1S alloy sample of PLGA coating, soak after 28 days in the 37oC normal saline, measuring its degradation rate by weight-loss method is 0.0411mm/year, is 4 times of no coating Fe-30Mn-1S alloy sample degradation speed.
Embodiment 5
At first, be that 90,000 PHA is dissolved in the ethyl acetate with molecular weight, concentration is 1w/v%, prepares the PHA coating by dip coating at the Fe-30Mn-1Pt alloy surface then, thickness is 15.3 μ m.Air drying 10 hours.
Apply the Fe-30Mn-1Pt alloy sample of PHA coating, soak after 28 days in the 37oC normal saline, measuring its degradation rate by weight-loss method is 0.0341mm/year, is 3 times of no coating Fe-30Mn-1Pt alloy sample degradation speed.
Embodiment 6
At first, be that 120,000 PEA is dissolved in the ethyl acetate with molecular weight, concentration is 0.5w/v%, goes out the PEA coating by spraying process in the pure iron surface preparation then, thickness is 20.6 μ m.Air drying 6 hours.
Apply the pure iron sample of PEA coating, soak after 28 days in the 37oC normal saline, measuring its degradation rate by weight-loss method is 0.0437mm/year, is 4 times of no coating pure iron sample degradation speed.
Embodiment 7
At first, be that 120,000 PCL is dissolved in the ethyl acetate with molecular weight, concentration is 2w/v%, goes out the PCL coating by spraying process in the pure iron surface preparation then, thickness is 19 μ m.Air drying 12 hours.
Apply the pure iron sample of PCL coating, soak after 28 days in the 37oC normal saline, measuring its degradation rate by weight-loss method is 0.0326mm/year, is 3.2 times of no coating pure iron sample degradation speed.
Embodiment 8
At first, with lactic acid and hydroxyacetic acid is that 100,000 PLGA is dissolved in the ethyl acetate for 85:15, molecular weight by weight proportion, concentration is 3w/v%, to be that the rapamycin medicine dissolution of 1:3 is in above-mentioned solution with the PLGA part by weight, go out the PLGA coating by spraying process in the pure iron surface preparation then, thickness is 24.2 μ m.At air drying after 24 hours, again vacuum drying 24 hours.
By efficient liquid phase chromatographic analysis, coating is soaked after 28 days in the 37oC normal saline, has 75% rapamycin to discharge.The degradation rate of measuring the pure iron sample that applies the PLGA coating by weight-loss method is 0.0427mm/year, is 4.2 times of no coating pure iron sample degradation speed.
Embodiment 9
At first, by weight proportion for 85:15, molecular weight are that 120,000 PLGA and 0.4g PCL are dissolved in the ethyl acetate, concentration is 0.8w/v%, goes out the PLGA coating by spraying process in the pure iron surface preparation then with the lactic acid of 2g and hydroxyacetic acid, and thickness is 20.3 μ m.After 24 hours, vacuum drying is 24 hours again at air drying.
According to the vitro cytotoxicity test of ISO10993 and GB/T16886.5, the cytotoxicity grade of the pure iron sample after the coating PLGA coating is 1 grade, and the cell grade of no coating pure iron sample is 2 grades, and this coating has obviously improved the cell compatibility of pure iron.
Embodiment 10
At first, be that 85:15, molecular weight are that 120,000 PLGA and 0.2gPEG are dissolved in the 20mL ethyl acetate with the lactic acid of 2g and hydroxyacetic acid part by weight, then by spraying process in pure iron coronary artery bracket surface preparation coating, coating layer thickness is 18 μ m.At air drying after 24 hours, in a vacuum dry 24 hours again.
Support is after holding, expand through overvoltage, and coating surface flawless, phenomenon such as come off show excellent non-deformability.Apply the pure iron support of PLGA coating, soak after 28 days in the 37oC normal saline, measuring its degradation rate by weight-loss method is 0.0421mm/year, is 4.2 times of no coating pure iron scaffold degradation speed.
Claims (6)
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Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102961787A (en) * | 2012-12-13 | 2013-03-13 | 北京大学 | Iron-based composite material used for full-degradation cardiovascular support and preparation method thereof |
| CN104587534A (en) * | 2013-10-31 | 2015-05-06 | 先健科技(深圳)有限公司 | An absorbable iron-base alloy support |
| CN104826173A (en) * | 2015-04-13 | 2015-08-12 | 西北工业大学 | Porous scaffold having double-layer or multi-layer framework structure, and preparation method thereof |
| JP2015524880A (en) * | 2012-07-10 | 2015-08-27 | フォート ウェイン メタルス リサーチ プロダクツ コーポレーション | Biodegradable alloy wire for medical devices |
| CN105708588A (en) * | 2016-01-19 | 2016-06-29 | 杨首男 | Degradable prostate stent |
| CN105797220A (en) * | 2014-12-31 | 2016-07-27 | 先健科技(深圳)有限公司 | Degradable ferrous alloy stent |
| WO2017000736A1 (en) * | 2015-07-01 | 2017-01-05 | 先健科技(深圳)有限公司 | Iron-based absorbable and implantable medical device and manufacturing method thereof |
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