WO2017124613A1 - 一种全降解镁合金及其制备方法 - Google Patents

一种全降解镁合金及其制备方法 Download PDF

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Publication number
WO2017124613A1
WO2017124613A1 PCT/CN2016/075396 CN2016075396W WO2017124613A1 WO 2017124613 A1 WO2017124613 A1 WO 2017124613A1 CN 2016075396 W CN2016075396 W CN 2016075396W WO 2017124613 A1 WO2017124613 A1 WO 2017124613A1
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magnesium alloy
alloy
magnesium
fully degraded
lanthanum
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PCT/CN2016/075396
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English (en)
French (fr)
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周倩
蒋宇钢
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周倩
蒋宇钢
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Priority to US15/781,151 priority Critical patent/US20190153570A1/en
Publication of WO2017124613A1 publication Critical patent/WO2017124613A1/zh

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
    • C22C—ALLOYS
    • C22C23/00—Alloys based on magnesium
    • C22C23/06—Alloys based on magnesium with a rare earth metal as the next major constituent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • C—CHEMISTRY; METALLURGY
    • C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
    • C22C—ALLOYS
    • C22C1/00—Making non-ferrous alloys
    • C22C1/02—Making non-ferrous alloys by melting
    • C22C1/03—Making non-ferrous alloys by melting using master alloys
    • C—CHEMISTRY; METALLURGY
    • C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
    • C22C—ALLOYS
    • C22C23/00—Alloys based on magnesium
    • C22C23/04—Alloys based on magnesium with zinc or cadmium as the next major constituent
    • C—CHEMISTRY; METALLURGY
    • C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
    • C22F—CHANGING THE PHYSICAL STRUCTURE OF NON-FERROUS METALS AND NON-FERROUS ALLOYS
    • C22F1/00—Changing the physical structure of non-ferrous metals or alloys by heat treatment or by hot or cold working
    • C22F1/06—Changing the physical structure of non-ferrous metals or alloys by heat treatment or by hot or cold working of magnesium or alloys based thereon

Definitions

  • This invention relates to the field of biological materials, and more particularly to a fully degradable magnesium alloy.
  • Cardiovascular and cerebrovascular diseases have attracted much attention due to their high incidence and high lethality and disability. Stent placement and reconstruction of blood supply is an important means of clinical treatment of ischemic cardiovascular and cerebrovascular diseases.
  • the main role of the stent in the blood vessels is to provide mechanical support to prevent elastic retraction and negative remodeling of the blood vessels.
  • the diseased arteries generally complete vascular remodeling and repair within 6-12 months. After this time, the stent has no benefit to the human body. Instead, the compression and stimulation of the vessel wall creates a series of problems.
  • the clinical application of vascular stent materials in China and abroad is mainly 316L stainless steel, cobalt-chromium alloy and nickel-titanium alloy.
  • the ideal vascular stent should be able to degrade and absorb after vascular repair.
  • the advantages of degradable stents are obvious: First, after the stents are degraded and absorbed, no foreign matter remains, reducing the risk factors for thrombosis; secondly, shortening the time of dual antiplatelet treatment and reducing bleeding and other related complications. From a physiological point of view, the disappearance of a hard stent is beneficial for restoring vascular tone and expansion and remodeling. In the long run, degradable stents will not affect the follow-up treatment of coronary heart disease, such as PCI, coronary artery bypass or drug-dissolving plaque. In addition, the degradable stent does not interfere with CT or MR imaging, eliminating the anxiety of a few patients carrying implants for life.
  • the polymer material is not developed under the X-ray, the radial support strength is insufficient, and the deformation ability is poor, which limits its application.
  • Ferroalloys are slow in corrosion in physiological environments, and corrosion products block blood vessels, so iron alloys are not suitable for degradable vascular stents.
  • magnesium alloys still have some problems as degradable vascular stents, such as excessive degradation, resulting in rapid loss of strength, intimal hyperplasia resulting in narrow stenosis, low strength resulting in early rebound, and the biocompatibility of magnesium alloy itself. The exact wait is urgent.
  • the object of the present invention is to provide a fully degraded magnesium alloy and a preparation method thereof.
  • the present invention has developed a fully degradable magnesium alloy with more controllable degradation rate and better biocompatibility for the requirements of cardiovascular and cerebrovascular stents.
  • a fully degraded magnesium alloy comprising magnesium and an alloying element, and the weight ratio of magnesium is not less than 85%, and the alloy is free of any one of cerium, lanthanum, cerium, lanthanum, cerium, lanthanum and zinc or Several combinations.
  • the weight ratios of lanthanum, cerium, lanthanum, cerium, lanthanum, cerium, lanthanum, cerium, and zinc are at most 10.0%, 15.0%, 15.0%, 7.0%, 4.0%, 12.0%, and 5.0%, respectively.
  • the weight ratios of lanthanum, cerium and lanthanum are at least 0.1%, 0.1% and 0.1%, respectively.
  • active elements include any one or a combination of two of titanium, potassium, barium, zirconium, calcium, lithium, aluminum, manganese.
  • the weight ratio of the elements is at most 2%.
  • a method for preparing a fully degraded magnesium alloy comprising the steps of:
  • the raw material is added into an electric resistance furnace for melting, and the process is carried out under a protective gas, refining, pouring, cooling into an ingot, solution treatment, and then plastically deforming and refining the alloy crystal grains, and then performing heat treatment to obtain a fully degraded magnesium alloy billet. .
  • the melting temperature of the alloy is 720 to 820 °C.
  • the casting temperature of the alloy is 700 to 760 °C.
  • the conditions for solid solution are 500 to 550 ° C for 4 to 24 hours.
  • a magnesium, an alloying element, and an active element and a weight ratio of magnesium of not less than 85%, and the alloy is not included in any one or a combination of lanthanum, cerium, lanthanum, cerium, lanthanum, cerium, and zinc;
  • the active element includes any one or a combination of two of titanium, potassium, barium, zirconium, calcium, lithium, aluminum, manganese, and the active element content is 0 to 2% by weight; and magnesium, aluminum and zinc are made of metal. The form is added, and the other elements are added by means of an intermediate alloy.
  • the invention has the advantages that the intrinsic corrosion resistance of the fully degraded magnesium alloy of the invention is similar to that of the high purity magnesium by the in vitro immersion corrosion test and the electrochemical corrosion test, and the in vitro cytotoxicity test of the fully degraded magnesium alloy shows good biocompatibility.
  • the degradation rate is controllable and the biocompatibility is good.
  • Table 1 shows Examples 1 to 71 of a fully degraded magnesium alloy of the present invention, which are prepared to obtain a fully degraded magnesium alloy of the present invention.
  • Table 1 shows the components of Examples 1 to 71 of the present invention.
  • Table 2 shows a fully degraded magnesium alloy examples 72-110 of the present invention which were prepared to obtain the fully degraded magnesium alloy of the present invention.
  • Table 2 shows the components of Examples 72 to 110 of the present invention.
  • Table 3 shows a fully degraded magnesium alloy examples 111 to 135 of the present invention which were prepared to obtain the fully degraded magnesium alloy of the present invention.
  • Table 3 shows the components of Examples 111 to 135 of the present invention.
  • the invention also discloses a preparation method of a fully degraded magnesium alloy, comprising the following steps:
  • the raw material is added into an electric resistance furnace for melting, and the process is carried out under a protective gas, refining, pouring, cooling into an ingot, solution treatment, and then plastically deforming and refining the alloy crystal grains, and then performing heat treatment to obtain a fully degraded magnesium alloy billet.
  • the melting temperature of the alloy is 720 to 820 °C.
  • the casting temperature of the alloy is 700 to 760 °C.
  • the conditions for solid solution are 500 to 550 ° C for 4 to 24 hours.
  • a magnesium, an alloying element, and an active element and a weight ratio of magnesium of not less than 85%, and the alloy is not included in any one or a combination of lanthanum, cerium, lanthanum, cerium, lanthanum, cerium, and zinc;
  • the active element includes any one or a combination of two of titanium, potassium, barium, zirconium, calcium, lithium, aluminum, manganese, and the active element content is 0 to 2% by weight; and magnesium, aluminum and zinc are made of metal. The form is added, and the other elements are added by means of an intermediate alloy.
  • the fully degraded magnesium alloy has excellent mechanical properties.
  • the fully degraded magnesium alloy of Example 110 was subjected to a soak corrosion test and an in vitro cytotoxicity test.
  • Immersion corrosion was performed in accordance with ASTM G31-72.
  • a fully degraded magnesium alloy metal sheet having a diameter of 8 mm and a thickness of 5 mm was polished to a smooth condition with 1200 Grit sandpaper, and then ultrasonically washed in acetone, absolute ethanol, and distilled water, respectively.
  • the weight and surface area of the metal were recorded, and the fully degraded magnesium alloy cylindrical piece was irradiated and sterilized under ultraviolet light, and each side was irradiated for 30 minutes.
  • the metal piece was put into a test tube containing DMEM + 10% FBS + 1% penicillin / streptomycin, the ratio of the solution volume to the metal surface area was 20 mL / cm 2 , and the test tube was placed in a 37 ° C, 5% CO 2 incubator. After 1 week, 2 weeks, and 3 weeks, the metal pieces were taken out and washed with double distilled water, and dried at room temperature. The corrosion products deposited on the surface of the sample were removed by washing with 200 g/L chromic acid, and the surface morphology of the sample was observed by scanning electron microscopy.
  • HUVEC-12 cells and HASMC cells in logarithmic growth phase were inoculated into 96-well flat-bottomed plates at a concentration of 3 ⁇ 10 4 /ml, each group was parallel 5 wells, 100 ⁇ L of cell suspension per well, a total of 6 groups, each Seed cells were seeded 2 plates.
  • the 96-well flat-bottomed plate inoculated with the cells was cultured in a 37 ° C, 95% relative humidity, 5% CO 2 incubator for 24 hours to allow the cells to grow adherently.
  • the 96-well culture plate was taken out, the culture solution was aspirated, and different concentrations of the extract were added to the 96-well plate.
  • the negative control group was added to the complete medium of 1640/DMEM, and the positive control group was added with the medium of 0.64% phenol.
  • the 96-well culture plate was cultured in a 37 ° C, 5% CO 2 incubator. Take a 96-well culture plate on the 1st and 3rd day respectively, add 10uL MTT (5mg/L) to each well, continue to culture in CO 2 incubator for 4h, then discard the original culture medium containing MTT and add DMSO. 150 ⁇ L, shaking at room temperature for 10 min under shaking at room temperature for 10 min to fully dissolve the crystal, and measuring the OD value of each well at a wavelength of 490 nm with a microplate reader.
  • the formula for calculating the relative proliferation rate of cells is:
  • ODt represents the average absorbance value of the experimental group
  • ODn represents the average absorbance value of the negative control group
  • the results of the experiment showed that the extracts of the fully degraded magnesium alloy were contacted with HASMC and HUVEC-12 cells for 1 d, respectively. After 3 days, the RGR of the extracts in different concentrations was greater than 75%, which was not significantly different from the negative control group.
  • the degraded magnesium alloy extract showed no toxic effect on the above two kinds of cells, and did not show an increase in toxicity with the prolongation of the incubation time; nor did it exhibit the effect of promoting the growth and proliferation of the two cells.
  • the cytotoxicity results of fully degraded magnesium alloys meet the requirements for biomedical materials used in vivo.
  • the in vitro cytotoxicity test of the fully degraded magnesium alloy showed good biocompatibility. It can be used as a preparation material for medical devices such as skull locks that can absorb blood vessels.
  • the fully degraded magnesium alloy has excellent mechanical properties.
  • the fully degraded magnesium alloy of Example 135 was subjected to a soak corrosion test and an in vitro cytotoxicity test.
  • Immersion corrosion was performed in accordance with ASTM G31-72.
  • a fully degraded magnesium alloy metal sheet having a diameter of 8 mm and a thickness of 5 mm was polished to a smooth condition with 1200 Grit sandpaper, and then ultrasonically washed in acetone, absolute ethanol, and distilled water, respectively.
  • the weight and surface area of the metal were recorded, and the fully degraded magnesium alloy cylindrical piece was irradiated and sterilized under ultraviolet light, and each side was irradiated for 30 minutes.
  • the metal piece was put into a test tube containing DMEM + 10% FBS + 1% penicillin / streptomycin, the ratio of the solution volume to the metal surface area was 20 mL / cm 2 , and the test tube was placed in a 37 ° C, 5% CO 2 incubator. After 1 week, 2 weeks, and 3 weeks, the metal pieces were taken out and washed with double distilled water, and dried at room temperature. The corrosion products deposited on the surface of the sample were removed by washing with 200 g/L chromic acid, and the surface morphology of the sample was observed by scanning electron microscopy.
  • HUVEC-12 cells and HASMC cells in logarithmic growth phase were inoculated into 96-well flat-bottomed plates at a concentration of 3 ⁇ 10 4 /ml, each group was parallel 5 wells, 100 ⁇ L of cell suspension per well, a total of 6 groups, each Seed cells were seeded 2 plates.
  • the 96-well flat-bottomed plate inoculated with the cells was cultured in a 37 ° C, 95% relative humidity, 5% CO 2 incubator for 24 hours to allow the cells to grow adherently.
  • the 96-well culture plate was taken out, the culture solution was aspirated, and different concentrations of the extract were added to the 96-well plate.
  • the negative control group was added to the complete medium of 1640/DMEM, and the positive control group was added with the medium of 0.64% phenol.
  • the 96-well culture plate was cultured in a 37 ° C, 5% CO 2 incubator. Take a 96-well culture plate on the 1st and 3rd day respectively, add 10uL MTT (5mg/L) to each well, continue to culture in CO 2 incubator for 4h, then discard the original culture medium containing MTT and add DMSO. 150 ⁇ L, shaking at room temperature for 10 min under shaking at room temperature for 10 min to fully dissolve the crystal, and measuring the OD value of each well at a wavelength of 490 nm with a microplate reader.
  • the formula for calculating the relative proliferation rate of cells is:
  • ODt represents the average absorbance value of the experimental group
  • ODn represents the average absorbance value of the negative control group
  • the results of the experiment showed that the extracts of the fully degraded magnesium alloy were contacted with HASMC and HUVEC-12 cells for 1 d, respectively. After 3 days, the RGR of the extracts in different concentrations was greater than 75%, which was not significantly different from the negative control group.
  • Degraded magnesium alloy extract The above two cells showed no toxic effects, and no increase in toxicity occurred with prolonged incubation time; nor did they show an effect of promoting the growth and proliferation of both cells.
  • the cytotoxicity results of fully degraded magnesium alloys meet the requirements for biomedical materials used in vivo.
  • the in vitro cytotoxicity test of the fully degraded magnesium alloy showed good biocompatibility. It can be used as a preparation material for a medical device such as a skull lock that can absorb blood vessels, and the effect is superior to that of the embodiment 110.

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Abstract

提供了一种新型全降解镁合金心脑血管支架材料，一种全降解镁合金，包括镁和合金元素，且镁的重量比不少于85％，且所述合金无素包括钆、铒、铥、钇、钕、钬和锌中的任意一种或几种的组合。该全降解镁合金力学性能达到心脑血管生物支架要求，经体外浸泡腐蚀试验及电化学腐蚀试验证实其体外耐腐蚀性能良好，该全降解镁合金体外细胞毒性试验显示良好的生物相容性，且降解速度可控，生物相容性好。

Description

一种全降解镁合金及其制备方法 技术领域
本发明涉及生物材料领域，更确切地说是一种全降解镁合金。
背景技术
心脑血管因其高发病率和高致死、致残率而广受关注。支架置入重建血运是临床上治疗缺血性心脑血管疾病的重要手段。支架在血管内的主要作用是提供力学支撑，防止血管弹性回缩和负性重构，病变动脉一般在6-12月内完成血管重塑和修复，超过该时间，支架对人体已无益处，反而对血管壁的压迫和刺激会产生一系列问题。目前国内、外临床上应用的血管支架材料主要为316L不锈钢、钴铬合金以及镍钛合金等，这些永久的金属支架在长期的植入过程中，会存在如下问题：长期内皮功能紊乱、内皮化延迟、促凝、长期物理刺激、局部慢性炎症反应、延长双重抗血小板治疗、支架处血管与正常血管力学性能不匹配、阻塞分支血管，与青少年生长发育不一致，干扰CT和MR成像，更为严重的是丧失再次手术机会。
理想的血管支架应能在血管修复后降解吸收。与金属支架相比，可降解支架优势明显：首先，支架降解吸收后，无异物残留，减少促发血栓形成的危险因素；其次，缩短双重抗血小板治疗时间，减少出血等相关并发症发生。从生理学角度看，坚硬支架的消失有利于恢复血管张力和扩张重构。长期来看，可降解支架不会影响冠心病的后续治疗，如PCI、冠脉搭桥或药物溶解斑块。此外，可降解支架不会干扰CT或MR成像，可消除少数患者终身携带植入物的焦虑情绪。
因金属镁具有良好的生物相容性和机械特征(强度、弹性、延展性、稳定性)，金属镁成为目前可降解支架材料的研究热点。德国Biotronik公司的AMS(absorb metaL stent)血管支架已经推出两代用于临床试验，在澳大利亚、德国、比利时等七个国家八个医疗中心共同参加了临床试验，成功植入71例AMS血管支架，发现安全性良好，无死亡、无心肌梗死、无血栓形成，可用MRI/CT手段检测，术后四个月支架完全降解。
目前研究的血管支架可降解材料主要包括聚合物材料、铁合金和镁合金。聚合物材料因X线下不显影，径向支撑强度不足，变形能力差而限制其应用。铁合金在生理环境中腐蚀速度慢，腐蚀产物阻塞血管，故铁合金也不适用于可降解血管支架。因其良好的生物相容性和机械性，金属镁成为目前可降解支架材料的研究热点。国际上，目前仅德国学者采用镁合金WE43研制的血管支架进入临床实验阶段，多中心随机研究发现，可降解镁合金支架植入冠脉狭窄患者后早期可达到与普通金属支架等同的恢复血流的效果，并可在4个月后完全降解。在国内，尚无镁合金支架的临床应用报道，仅中科院金属研究所研制了一种可降解镁合金AZ31系列镁合金冠脉支架，并将12枚支架植入12只新西兰大白兔腹主动脉中，随访期内大白兔存活良好，支架植入部位血管通畅，无血栓形成，4个月后植入支架完全降解，从动物实验层面证实了可降解镁合金支架的安全性及有效性。然而，镁合金作为可降解血管支架仍存在一些问题，比如降解过快，造成强度损失较快，内膜层增生造成官腔狭窄，强度低造成早期回弹，以及镁合金本身的生物相容性不确切等，都亟待解决。
发明内容
本发明的目的是提供一种全降解镁合金及其制备方法，本发明针对心脑血管支架的要求，开发了一种降解速度更为可控、生物相容性更好的全降解镁合金。
本发明采用以下技术方案：
一种全降解镁合金，包括镁和合金元素，且镁的重量比不少于85％，且所述合金无素包括钆、铒、铥、钇、钕、钬和锌中的任意一种或几种的组合。
所述钆、铒、铥、钇、钕、钬和锌的重量比最大分别为10.0％、15.0％、15.0％、7.0％、4.0％、12.0％和5.0％。
所述钆、铒、铥的重量比最少分别为0.1％、0.1％和0.1％。
还包括活性元素，且活性元素包括钛、钾、锶、锆、钙、锂、铝、锰中的任意一种或两种的组合。
所述的元素的重量比最大为2％。
一种全降解镁合金的制备方法，包括以下步骤：
将原料加入电阻炉内进行熔炼，该过程在保护气体下进行，精炼后浇注，冷却成铸锭，固溶处理，然后进行塑性变形细化合金晶粒，再进行热处理后得到全降解镁合金坯料。
合金的熔炼温度为720～820℃。
合金的浇注温度为700～760℃。
固溶的条件为500～550℃处理4～24h。
镁、合金元素以及活性元素，且镁的重量比不少于85％，且所述合金无素包括钆、铒、铥、钇、钕、钬和锌中的任意一种或几种的组合；活性元素包括钛、钾、锶、锆、钙、锂、铝、锰中的任意一种或两种的组合，且活性元素含量的重量比为0～2％；且镁、铝和锌采用金属的形式加入，且其他元素则采用中间合金的方式加入。
本发明的优点是：本发明的全降解镁合金经体外浸泡腐蚀试验及电化学腐蚀试验证实其体外耐腐蚀性能与高纯镁相近，该全降解镁合金体外细胞毒性试验显示良好的生物相容性，且降解速度可控，生物相容性好。
具体实施方式
表1给出了本发明的一种全降解镁合金实施例1～71，制备可得到本发明的全降解镁合金。
表1给出了本发明的实施例1～71的组分
Figure PCTCN2016075396-appb-000001
Figure PCTCN2016075396-appb-000002
Figure PCTCN2016075396-appb-000003
Figure PCTCN2016075396-appb-000004
表2给出了本发明的一种全降解镁合金实施例72～110，制备可得到本发明的全降解镁合金。
表2给出了本发明的实施例72～110的组分
Figure PCTCN2016075396-appb-000005
Figure PCTCN2016075396-appb-000006
Figure PCTCN2016075396-appb-000007
表3给出了本发明的一种全降解镁合金实施例111～135，制备可得到本发明的全降解镁合金。
表3给出了本发明的实施例111～135的组分
Figure PCTCN2016075396-appb-000008
Figure PCTCN2016075396-appb-000009
Figure PCTCN2016075396-appb-000010
Figure PCTCN2016075396-appb-000011
本发明还公开了一种全降解镁合金的制备方法，包括以下步骤：
将原料加入电阻炉内进行熔炼，该过程在保护气体下进行，精炼后浇注，冷却成铸锭，固溶处理，然后进行塑性变形细化合金晶粒，再进行热处理后得到全降解镁合金坯料。合金的熔炼温度为720～820℃。合金的浇注温度为700～760℃。固溶的条件为500～550℃处理4～24h。镁、合金元素以及活性元素，且镁的重量比不少于85％，且所述合金无素包括钆、铒、铥、钇、钕、钬和锌中的任意一种或几种的组合；活性元素包括钛、钾、锶、锆、钙、锂、铝、锰中的任意一种或两种的组合，且活性元素含量的重量比为0～2％；且镁、铝和锌采用金属的形式加入，且其他元素则采用中间合金的方式加入。
表4全降解镁合金的制备工艺
Figure PCTCN2016075396-appb-000012
Figure PCTCN2016075396-appb-000013
浸泡腐蚀试验及结果
表5不同组分合金力学性能
合金编号 抗拉强度 屈服强度 延伸率
实施例96 270 203 15.2
实施例97 312 256 10.4
实施例98 252 207 10.2
实施例99 237 198 17.9
实施例100 249 202 19.1
实施例101 223 182 25.2
实施例102 265 213 17.0
实施例103 213 172 27.1
实施例104 245 201 22.5
实施例105 315 252 11.3
实施例106 261 204 18.2
实施例107 312 263 11.7
实施例108 211 165 24.7
实施例109 321 268 12.1
从上表可以看出，全降解镁合金力学性能优异。
将实施例110的全降解镁合金，进行浸泡腐蚀试验及和体外细胞毒性试验。
浸泡腐蚀试验及结果
浸泡腐蚀根据ASTM G31-72标准执行。将直径8mm，厚5mm的全降解镁合金金属片用1200Grit砂纸打磨至光滑，然后依次在丙酮，无水乙醇，蒸馏水中分别超声清洗。记录金属的重量及表面积，将全降解镁合金圆柱片置于紫外线下照射灭菌，每面各照射30min。金属片投入含DMEM+10％FBS+1％青霉素/链霉素双抗试管中，溶液体积与金属表面积之比为20mL/cm2，将试管置于37℃、5％CO2培养箱中，1周、2周、3周后分别取出，双蒸水冲洗金属片，室温下干燥。用200g/L铬酸清洗去除试样表面沉积的腐蚀产物，扫描电镜观察试样表面形貌。根据ASTM G31-72腐蚀速率计算公式为：腐蚀速率＝(K×W)/(A×T×D)单位为mm/a，其中，K＝8.76×104，W为浸泡前后质量差(g)，A为试样与溶液接触的表面积(cm2)，T为浸泡时间(h)，D为试样密度(g/cm3)。
表6全降解镁合金、镁合金AZ31、纯镁体外降解速率(mm/a)
Tab.6Corrosion rate of Mg-RE，镁合金AZ31and pure Mg(mm/a)
Figure PCTCN2016075396-appb-000014
从表6可以看出，全降解镁合金、镁合金AZ31、纯镁浸泡于模拟体液中第1、2、3周后的降解速率表6所示，结果表明全降解镁合金在3个时间点的降解速率均远比镁合金AZ31慢，而和纯镁降解速率相近。该全降解镁合金经体外浸泡腐蚀试验及电化学腐蚀试验证实其体外耐腐蚀性能与高纯镁相近，优于镁合金AZ31。
体外细胞毒性试验及结果
设不同浓度的浸提液组及阴性、阳性对照组。向RPMI1640/DMEM培养基中加入10％的FBS及1％青霉素/链霉素双抗(RPMI1640用于培养HUVEC-12，DMEM用于培养HASMC)。将全降解镁合金圆柱片置于紫外线下照射灭菌，每面各照射30min。然后将镁合金全降解镁合金圆柱片置于含RPMI1640完全培养基/DMEM完全培养基中的试管中，试样表面积与培养基体积之比为 1.25cm2/mL，置于37℃、95％相对湿度、5％CO2培养箱中72h，然后将镁合金全降解镁合金圆柱片取出，得到材料浸提液原液(100％M)，浸提液用完全培养基稀释成50％M，25％M，10％M。分别取对数生长期的HUVEC-12细胞、HASMC细胞以3×104个/ml的浓度接种于96孔平底培养板，每组平行5孔，每孔100μL细胞悬液，共6组，每种细胞接种2板。将接种好细胞的96孔平底培养板置于37℃、95％相对湿度、5％CO2培养箱中培养24h，使细胞贴壁生长。取出96孔培养板，吸弃培养液，向96孔板中加入不同浓度的浸提液，阴性对照组加入1640/DMEM完全培养基，阳性对照组加入0.64％苯酚的培养基。加完液体以后96孔培养板置于37℃、5％CO2培养箱中培养。分别于第1、3天各取一块96孔培养板，向每孔中加入10uL MTT(5mg/L)，继续在CO2培养箱中培养4h，然后吸弃含MTT的原培养液，加入DMSO 150μL，室温避光条件下在摇床上小幅度震荡10min，使结晶充分溶解，用酶标仪在490nm波长测量各孔OD值。
细胞相对增殖率计算公式为：
RGR＝(ODt/ODn)×100％
其中ODt表示实验组平均吸光度值，ODn表示阴性对照组平均吸光度值
结果：
表7HASMC在不同浓度的全降解镁合金浸提液中的吸光度值和细胞相对增殖率
Tab.7OD vaLue and RGR of HASMC i n different Mg-RE extracts
Figure PCTCN2016075396-appb-000015
Figure PCTCN2016075396-appb-000016
表8HUVEC-12在不同浓度的全降解镁合金浸提液中的吸光度值和细胞相对增殖率
Tab.8OD vaLue and RGR of HUVEC-12in different Mg-RE extracts
Figure PCTCN2016075396-appb-000017
实验的结果表明，全降解镁合金的浸提液分别与HASMC、HUVEC-12细胞接触培养1d，3d后，不同浓度浸提液组的RGR均大于75％，与阴性对照组无显著差别，全降解镁合金浸提液对上述两种细胞没有表现出毒性作用，随着孵育时间延长未出现毒性增加的现象；也没表现出促进两种细胞生长增殖的作用。全降解镁合金的细胞毒性结果符合在体内使用的生物医用材料要求。该全降解镁合金体外细胞毒性试验显示良好的生物相容性。可作为可吸收血管之间，可吸收颅骨锁等医疗器械的制备材料。
浸泡腐蚀试验及结果
表9不同组分合金力学性能
合金编号 抗拉强度 屈服强度 延伸率
实施例135 335 278 14.2
从上表可以看出，全降解镁合金力学性能优异。
将实施例135的全降解镁合金，进行浸泡腐蚀试验及和体外细胞毒性试验。
浸泡腐蚀试验及结果
浸泡腐蚀根据ASTM G31-72标准执行。将直径8mm，厚5mm的全降解镁合金金属片用1200Grit砂纸打磨至光滑，然后依次在丙酮，无水乙醇，蒸馏水中分别超声清洗。记录金属的重量及表面积，将全降解镁合金圆柱片置于紫外线下照射灭菌，每面各照射30min。金属片投入含DMEM+10％FBS+1％青霉素/链霉素双抗试管中，溶液体积与金属表面积之比为20mL/cm2，将试管置于37℃、5％CO2培养箱中，1周、2周、3周后分别取出，双蒸水冲洗金属片，室温下干燥。用200g/L铬酸清洗去除试样表面沉积的腐蚀产物，扫描电镜观察试样表面形貌。根据ASTM G31-72腐蚀速率计算公式为：腐蚀速率＝(K×W)/(A×T×D)
单位为mm/a，其中，K＝8.76×104，W为浸泡前后质量差(g)，A为试样与溶液接触的表面积(cm2)，T为浸泡时间(h)，D为试样密度(g/cm3)。
表10全降解镁合金、镁合金AZ31、纯镁体外降解速率(mm/a)
Tab.10 Corrosion rate of Mg-RE，镁合金AZ31and pure Mg(mm/a)
Figure PCTCN2016075396-appb-000018
从表10可以看出，全降解镁合金、镁合金AZ31、纯镁浸泡于模拟体液中第1、2、3周后的降解速率表10所示，结果表明全降解镁合金在3个时间点的降解速率均远比镁合金AZ31慢，而和纯镁降解速率相近。该全降解镁合金经体外浸泡腐蚀试验及电化学腐蚀试验证实其体外耐腐蚀性能与高纯镁相近，优于镁合金AZ31。
体外细胞毒性试验及结果
设不同浓度的浸提液组及阴性、阳性对照组。向RPMI1640/DMEM培养基中加入10％的FBS及1％青霉素/链霉素双抗(RPMI1640用于培养HUVEC-12，DMEM用于培养HASMC)。将全降解镁合金圆柱片置于紫外线下照射灭菌，每面各照射30min。然后将镁合金全降解镁合金圆柱片置于含RPMI1640完全培养基/DMEM完全培养基中的试管中，试样表面积与培养基体积之比为1.25cm2/mL，置于37℃、95％相对湿度、5％CO2培养箱中72h，然后将镁合金全降解镁合金圆柱片取出，得到材料浸提液原液(100％M)，浸提液用完全培养基稀释成50％M，25％M，10％M。分别取对数生长期的HUVEC-12细胞、HASMC细胞以3×104个/ml的浓度接种于96孔平底培养板，每组平行5孔，每孔100μL细胞悬液，共6组，每种细胞接种2板。将接种好细胞的96孔平底培养板置于37℃、95％相对湿度、5％CO2培养箱中培养24h，使细胞贴壁生长。取出96孔培养板，吸弃培养液，向96孔板中加入不同浓度的浸提液，阴性对照组加入1640/DMEM完全培养基，阳性对照组加入0.64％苯酚的培养基。加完液体以后96孔培养板置于37℃、5％CO2培养箱中培养。分别于第1、3天各取一块96孔培养板，向每孔中加入10uL MTT(5mg/L)，继续在CO2培养箱中培养4h，然后吸弃含MTT的原培养液，加入DMSO 150μL，室温避光条件下在摇床上小幅度震荡10min，使结晶充分溶解，用酶标仪在490nm波长测量各孔OD值。
细胞相对增殖率计算公式为：
RGR＝(ODt/ODn)×100％
其中ODt表示实验组平均吸光度值，ODn表示阴性对照组平均吸光度值
结果：
表11HASMC在不同浓度的全降解镁合金浸提液中的吸光度值和细胞相对增殖率
Tab.11OD vaLue and RGR of HASMC in different Mg-RE extracts
Figure PCTCN2016075396-appb-000019
Figure PCTCN2016075396-appb-000020
表12HUVEC-12在不同浓度的全降解镁合金浸提液中的吸光度值和细胞相对增殖率
Tab.12OD vaLue and RGR of HUVEC-12i n different Mg-RE extracts
Figure PCTCN2016075396-appb-000021
实验的结果表明，全降解镁合金的浸提液分别与HASMC、HUVEC-12细胞接触培养1d，3d后，不同浓度浸提液组的RGR均大于75％，与阴性对照组无显著差别，全降解镁合金浸提液对 上述两种细胞没有表现出毒性作用，随着孵育时间延长未出现毒性增加的现象；也没表现出促进两种细胞生长增殖的作用。全降解镁合金的细胞毒性结果符合在体内使用的生物医用材料要求。该全降解镁合金体外细胞毒性试验显示良好的生物相容性。可作为可吸收血管之间，可吸收颅骨锁等医疗器械的制备材料，且效果优于实施例110的的效果。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种全降解镁合金，其特征在于，包括镁和合金元素，且镁的重量比不少于85％，且所述合金无素包括钆、铒、铥、钇、钕、钬和锌中的任意一种或几种的组合。
  2. 根据权利要求1所述的全降解镁合金，其特征在于，所述钆、铒、铥、钇、钕、钬和锌的重量比最大分别为10.0％、15.0％、15.0％、7.0％、4.0％、12.0％和5.0％。
  3. 根据权利要求2所述的全降解镁合金，其特征在于，所述钆、铒、铥的重量比最少分别为0.1％、0.1％和0.1％。
  4. 根据权利要求1至3中任意一项所述的全降解镁合金，其特征在于，还包括活性元素，且活性元素包括钛、钾、锶、锆、钙、锂、铝、锰中的任意一种或两种的组合。
  5. 根据权利要求4所述的全降解镁合金，其特征在于，所述的元素的重量比最大为2％。
  6. 一种全降解镁合金的制备方法，其特征在于，包括以下步骤：
    将原料加入电阻炉内进行熔炼，该过程在保护气体下进行，精炼后浇注，冷却成铸锭，固溶处理，然后进行塑性变形细化合金晶粒，再进行热处理后得到全降解镁合金坯料。
  7. 根据权利要求6所述的制备方法，其特征在于，合金的熔炼温度为720～820℃。
  8. 根据权利要求6所述的制备方法，其特征在于，合金的浇注温度为700～760℃。
  9. 根据权利要求6所述的制备方法，其特征在于，固溶的条件为500～550℃处理4～24h。
  10. 根据权利要求6所述的制备方法，其特征在于，原料包括镁、合金元素以及活性元素，且镁的重量比不少于85％，且所述合金无素包括钆、铒、铥、钇、钕、钬和锌中的任意一种或几种的组合；活性元素包括钛、钾、锶、锆、钙、锂、铝、锰中的任意一种或两种的组合，且活性元素含量的重量比为0～2％；且镁、铝和锌采用金属的形式加入，且其他元素则采用中间合金的方式加入。
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