WO2015188403A1 - 用于神经缺损修复的可降解镁合金神经导管及其制备方法 - Google Patents

用于神经缺损修复的可降解镁合金神经导管及其制备方法 Download PDF

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Publication number
WO2015188403A1
WO2015188403A1 PCT/CN2014/080937 CN2014080937W WO2015188403A1 WO 2015188403 A1 WO2015188403 A1 WO 2015188403A1 CN 2014080937 W CN2014080937 W CN 2014080937W WO 2015188403 A1 WO2015188403 A1 WO 2015188403A1
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WIPO (PCT)
Prior art keywords
nerve
magnesium alloy
conduit
nerve conduit
defect repair
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PCT/CN2014/080937
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English (en)
French (fr)
Inventor
袁广银
丁文江
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上海交通大学
山东中保康医疗器具有限公司
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Application filed by 上海交通大学, 山东中保康医疗器具有限公司 filed Critical 上海交通大学
Priority to US15/775,008 priority Critical patent/US10792391B2/en
Publication of WO2015188403A1 publication Critical patent/WO2015188403A1/zh

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    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A61L27/047—Other specific metals or alloys not covered by A61L27/042 - A61L27/045 or A61L27/06
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/11—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis
    • A61B17/1128—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis of nerves
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00004—(bio)absorbable, (bio)resorbable, resorptive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/11—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis
    • A61B2017/1132—End-to-end connections
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/32—Materials or treatment for tissue regeneration for nerve reconstruction
    • 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

  • the invention relates to the field of biological material processing, in particular to a degradable magnesium alloy nerve conduit for nerve defect repair and a preparation method thereof.
  • the repair materials for peripheral nerve defects include autologous tissues (such as nerves, blood vessels, acellular matrix, etc.), but the source of autologous tissue is limited, and it will cause permanent damage to the donor site.
  • the most promising approach is to bridge the repair of nerve defects by tissue engineered artificial nerves constructed by catheters.
  • the current catheters used in nerve repair mainly focus on high molecular polymers, natural biological materials (such as collagen). Although these materials are excellent in biocompatibility, the degradation products are likely to cause inflammation of the surrounding tissues and collapse of the wall. The wall permeability is not good, and the degradation time is difficult to precisely control, which is not conducive to the regeneration of axons. Therefore, there is currently no ideal neurocatheter material widely used in clinical practice.
  • degradable metal-magnesium alloy materials have been used in human clinical trials as vascular stents. These metal materials not only have good biocompatibility, but also have suitable mechanical properties, strong wall support, and degradation. The rate is controllable, the degradation products are essential elements of the human body, and the biocompatibility is good. Moreover, recent studies have shown that the magnesium ions released during the degradation of magnesium alloys have a protective effect on apoptosis caused by nerve cell damage [History: Hasanein P. et al, Oral magnesium admini stration inhibition thermal hyperal gesia induced by diabetes in rats.
  • the present invention first proposes the use of a degradable metal magnesium-based catheter as a nerve conduit for the repair of peripheral nerve defects, and explores a new approach to tissue engineered artificial nerve repair.
  • the present invention provides a degradable magnesium alloy nerve conduit for nerve defect repair, wherein the nerve conduit is a round tube type, and a plurality of rows of through holes are arranged on a wall of the nerve conduit, each column of through holes Arranged at equal intervals along the axial direction of the circular tube, the through holes of adjacent columns are arranged in a wrong position.
  • the present invention also relates to the aforementioned method for preparing a degradable magnesium alloy nerve conduit for nerve defect repair, the method comprising the steps of:
  • Step 1 the magnesium alloy tube blank is machined at one end of a 45 ° cone surface, and extruded to obtain a magnesium alloy intermediate tube;
  • Step 2 the magnesium alloy intermediate tube is rolled and drawn after multiple passes to obtain a capillary tube;
  • Step 3 the capillary is subjected to stress relief annealing, heat preservation, laser cutting, and punching to obtain a porous catheter;
  • Step 4 the porous catheter is pickled in an ultrasonic cleaning machine, and electrochemically polished, that is, it can be used for nerve defect repair. Degradation of magnesium alloy nerve conduits.
  • the magnesium alloy tube blank has an outer diameter of 02 mm, the extrusion temperature is 300 to 400 ° C, and the outer diameter of the magnesium alloy intermediate tube is 06 to 08, and the wall thickness is 0. 5 ⁇ 1
  • spray a boron nitride spray on the inner and outer walls of the mold and the magnesium alloy tube blank as a lubricant Let, before extrusion, spray a boron nitride spray on the inner and outer walls of the mold and the magnesium alloy tube blank as a lubricant.
  • the outer diameter of the capillary is 0. 1 ⁇ 0. 2mm.
  • the temperature of the stress relief annealing is 300 ⁇ 350 °C, and the heat preservation time is 20 ⁇
  • the pickling is specifically: ultrasonic pickling in an acid washing solution for 5 to 30 minutes.
  • the pickling solution comprises the following components: phosphoric acid 80 ⁇ 100 ml/L, ammonium hydrogen fluoride 40 ⁇ 60 g/L, and the solvent is deionized water.
  • the polishing liquid used in the electrochemical polishing treatment is phosphoric acid: anhydrous ethanol is 1:1 or ethylene glycol ether: hydrochloric acid is 9:1, and the polishing treatment voltage is 2 to 8 V.
  • the polishing treatment time is 20 to 240 s, and the polishing treatment temperature is room temperature.
  • the present invention has the following beneficial effects:
  • the preparation method of the invention has simple process, and the prepared degradable magnesium alloy nerve conduit for nerve defect repair has uniform wall thickness and smooth surface.
  • the degradable magnesium alloy nerve conduit for repairing nerve defects of the present invention has excellent biocompatibility, good lumen support effect, good permeability of the perforated tube wall, and is favorable for regeneration of axons, the present invention
  • a tissue engineered artificial nerve repair system constructed using a porous degradable magnesium alloy nerve conduit to bridge the repair of nerve defects.
  • the magnesium metal material used in the invention has good electrical conductivity, and an applied electric field can be applied on the implanted magnesium alloy nerve conduit to electrically stimulate the nerve defect region to further induce nerve growth factor in the damaged region (nerve growth).
  • the expression of factor, NGF which creates a microenvironment that is conducive to nerve regeneration.
  • the degradation of the magnesium alloy material used in the present invention causes a weak alkaline environment in the local micro-region of the human body, which is beneficial to inhibit the growth of bacteria, and can achieve the purpose of antibacterial and anti-inflammatory in a certain period of time after the operation.
  • the tube wall of the degradable magnesium alloy nerve conduit for nerve defect repair of the present invention uniformly distributes a certain number of holes, which is beneficial to the nutrient exchange between the peripheral nerve of the defect and the surrounding tissue outside the tube wall, and the catheter wall is distributed with a certain number of holes.
  • the pores also function to regulate the rate of degradation, which is beneficial to match the time required for nerve regeneration and the time of catheter degradation.
  • the degradable magnesium alloy nerve conduit for nerve defect repair of the present invention adopts a suitable toughness and demagnetizable magnesium alloy material, and can satisfy sufficient wall support strength to prevent collapse.
  • FIG. 1 is a 3D effect diagram of a degradable magnesium alloy nerve conduit for nerve defect repair in the present invention
  • FIG. 2 is a 6 mm defect of a sciatic nerve implanted in an adult SD rat with a degradable magnesium alloy nerve conduit for nerve defect repair according to the present invention
  • FIG. 3 is a schematic view showing the implantation of a degradable magnesium alloy nerve conduit for nerve defect repair in a sciatic nerve defect of an adult SD rat for 2 months;
  • Figure 4 is a photograph of a rat toe; wherein a is the experimental side; b is the healthy side;
  • Figure 5 is a HE staining of the cross section and longitudinal section of the regenerative nerve.
  • the left picture shows the HE staining of the transverse section of the regenerative nerve, and the right picture shows the HE staining of the longitudinal section.
  • the present invention relates to a degradable magnesium alloy nerve conduit for use in the repair of a nerve defect, the structure of which is shown in Fig. 1, the length is 6 let, the outer diameter is 2, and the wall thickness is 0.2.
  • the column of the nerve conduit is provided with four rows of through holes, and the through holes of each column are arranged at equal intervals along the axial direction of the circular tube, and the through holes of adjacent columns are arranged in a wrong position, and the number of through holes in each column is six, and the apertures are all For 0. 3 let.
  • the present embodiment relates to the aforementioned method for preparing a degradable magnesium alloy nerve conduit for nerve defect repair, the method comprising the steps of:
  • the first step of the first step of the outer diameter of the 20 mm of the Mg-Nd-Zn-Zr magnesium alloy tube blank is processed to a 45 ° cone surface, and the temperature is 400 ° C, the magnesium alloy intermediate tube 08x0. 5mm (outer diameter X wall thickness);
  • Step 2 the capillary tube having an outer diameter of 2 mm and a wall thickness of 0.2 mm is obtained by rolling and drawing the intermediate tube of the magnesium alloy;
  • Step 3 The capillary is subjected to stress relief annealing at a temperature of 300 ° C for 30 minutes, laser cutting, punching, and obtaining a porous conduit;
  • Step 4 The porous catheter is pickled in an ultrasonic cleaner for 5 to 30 minutes (the acid washing solution includes the following components: phosphoric acid 80 to 100 ml/L, ammonium hydrogen fluoride 40 to 60 g/L, and the solvent is deionized. Water.), Electrochemical polishing treatment (using a polishing solution for phosphoric acid: absolute ethanol volume ratio of 1:1) The polishing treatment voltage is 2 to 8 V, and the polishing treatment time is 20 to 240 s, at room temperature, ie A degradable magnesium alloy nerve conduit for nerve defect repair is available.
  • the acid washing solution includes the following components: phosphoric acid 80 to 100 ml/L, ammonium hydrogen fluoride 40 to 60 g/L, and the solvent is deionized. Water.
  • Electrochemical polishing treatment using a polishing solution for phosphoric acid: absolute ethanol volume ratio of 1:1
  • the polishing treatment voltage is 2 to 8 V
  • the polishing treatment time is 20 to 240 s, at room temperature, ie
  • the embodiment relates to a degradable magnesium alloy nerve conduit for repairing a nerve defect, and the structure thereof is as shown in FIG. 1 , the length is 50, the wall thickness is 0.15 mm, and the outer diameter is 3, which is a circular tube type.
  • the column of the nerve conduit is provided with 8 rows of through holes, and the through holes of each column are arranged at equal intervals along the axial direction of the circular tube, and the through holes of adjacent columns are arranged in a wrong position, and the number of through holes in each column is 50, and the apertures are all 0. 03mm.
  • the present embodiment relates to the aforementioned method for preparing a degradable magnesium alloy nerve conduit for nerve defect repair, and the method includes the following steps:
  • the first intermediate portion of the Mg-Zn-Zr magnesium alloy tube having a diameter of 20 mm is machined to a 45 ° cone surface, and extruded at a temperature of 300 ° C to obtain a magnesium alloy intermediate tube 07x0. 8 mm (outer Diameter X wall thickness);
  • the capillary tube having an outer diameter of 3 mm and a wall thickness of 0.15 mm is obtained by rolling and drawing the magnesium alloy intermediate tube through a plurality of passes;
  • Step 3 The capillary is subjected to stress relief annealing at a temperature of 350 ° C for 20 min, laser cutting, and punching to obtain a porous conduit;
  • Step 4 The porous catheter is pickled in an ultrasonic cleaner for 5 to 30 minutes (the acid washing solution includes the following components: phosphoric acid 80 to 100 ml/L, ammonium hydrogen fluoride 40 to 60 g/L, and the solvent is deionized. Water.), Electrochemical polishing treatment (using a polishing solution of ethylene glycol ether: hydrochloric acid volume ratio of 9:1) The polishing treatment voltage is 2 to 8 V, and the polishing treatment time is 20 to 240 s, at room temperature. A degradable magnesium alloy nerve conduit for nerve defect repair is available.
  • the acid washing solution includes the following components: phosphoric acid 80 to 100 ml/L, ammonium hydrogen fluoride 40 to 60 g/L, and the solvent is deionized. Water.
  • Electrochemical polishing treatment using a polishing solution of ethylene glycol ether: hydrochloric acid volume ratio of 9:1
  • the polishing treatment voltage is 2 to 8 V
  • the polishing treatment time is 20 to 240 s
  • the present embodiment relates to a degradable magnesium alloy nerve conduit for repairing a nerve defect, the structure of which is shown in Fig. 1.
  • the length is 5, the wall thickness is 0. 10 let, the outer diameter is 1 for the round tube type,
  • the column of the nerve conduit is provided with four rows of through holes, and the through holes of each column are arranged at equal intervals along the axial direction of the circular tube, and the through holes of adjacent columns are arranged in a wrong position, and the number of through holes in each column is five, and the aperture is For 0. 2 let.
  • the present embodiment relates to the aforementioned method for preparing a degradable magnesium alloy nerve conduit for nerve defect repair, the method comprising the steps of:
  • Step 1 The end of the Mg-Zn-Mn magnesium alloy tube with an outer diameter of 20 mm is machined to a 45 ° cone surface and extruded at a temperature of 320 ° C to obtain a magnesium alloy intermediate tube of 06 x 1 mm (outer diameter X). Wall thickness);
  • Step 2 after the magnesium alloy intermediate pipe is rolled and drawn in multiple passes, a capillary having an outer diameter of lmm and a wall thickness of 0.10 mm is obtained;
  • Step 3 The capillary is subjected to stress relief annealing at a temperature of 300 ° C for 25 min, laser cutting, and punching to obtain a porous conduit;
  • Step 4 The porous catheter is pickled in an ultrasonic cleaner for 5 to 30 minutes (the acid washing solution includes the following components: phosphoric acid 80 to 100 ml/L, ammonium hydrogen fluoride 40 to 60 g/L, and the solvent is deionized. Water.), Electrochemical polishing treatment (using a polishing solution for phosphoric acid: absolute ethanol volume ratio of 1:1) The polishing treatment voltage is 2 to 8 V, and the polishing treatment time is 20 to 240 s, at room temperature, ie A degradable magnesium alloy nerve conduit for nerve defect repair is available.
  • the acid washing solution includes the following components: phosphoric acid 80 to 100 ml/L, ammonium hydrogen fluoride 40 to 60 g/L, and the solvent is deionized. Water.
  • Electrochemical polishing treatment using a polishing solution for phosphoric acid: absolute ethanol volume ratio of 1:1
  • the polishing treatment voltage is 2 to 8 V
  • the polishing treatment time is 20 to 240 s, at room temperature, ie

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Abstract

一种用于神经缺损修复的可降解镁合金神经导管及其制备方法；所述神经导管为圆管型，所述神经导管的管壁上设置有多列通孔，每列通孔沿圆管轴向等间距排布，相邻列的通孔错位排列。该神经导管的制备方法包括如下步骤：步骤1，将镁合金管坯一端加工出45°的锥面，进行挤压，得镁合金中间管材；步骤2，将镁合金中间管材经多道次轧制、拉拔后，得毛细管；步骤3，将毛细管进行去应力退火，保温，激光切割，打孔，得多孔导管；步骤4，将多孔导管在超声清洗机中酸洗，电化学抛光处理，即可。该方法工艺简单，制备出的用于神经缺损修复的多孔可降解镁合金神经导管壁厚均匀、表面光滑。

Description

用于神经缺损修复的可降解镁合金神经导管及其制备方法 技术领域
本发明涉及的是生物材料加工领域，具体为一种用于神经缺损修复的可降解镁合 金神经导管及其制备方法。 说
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周围神经缺损的修复材料有自体组织 （如神经， 血管， 脱细胞基质等） ， 然而 自体组织来源有限， 且会造成供区的永久性损伤。 通过导管构建的组织工程化人工 神经来桥接修复神经缺损是最具前景的方法。 书目前应用于神经修复的导管主要集中 在高分子聚合物， 天然生物材料（如胶原蛋白等） ， 这些材料虽然生物相容性优良， 但是降解产物容易导致周围组织的炎症反应及管壁塌陷， 管壁通透性不佳， 降解时 间难以精确调控， 不利于神经轴突的再生。 因此目前临床上还没有一种理想的神经 导管材料被广泛采用。
随着材料科学的进步， 可降解金属镁合金材料作为血管支架已应用于人体临床 试验， 该类金属材料不仅具有良好的生物相容性， 而且具有适宜的力学性能， 管壁 支撑作用强， 降解速率可控， 降解产物为人体必需元素， 生物相容性好。 而且近年 来研究表明镁合金降解过程中释放的镁离子具有对神经细胞损伤引起的凋亡具有 保护作用 【文献： Hasanein P. et al, Oral magnesium admini stration prevents thermal hyperal gesia induced by diabetes in rats. Diabetes Res Cl in Pract (2006) 73 (1) : 17-22】 ， 同时研究表明镁离子能改善大鼠因遭受外力受损的 神经学功能禾口记忆【文献： Jeong S. M, et al . Changes in magnesium concentration in the serum and cerebrospinal flui d of neuropathi c rats. Acta Anaesthesiol Scand (2006) . 50 (2) : 211-6 ] 。 采用激光加工技术， 能够精确制备多孔的组织工程 金属管状支架， 为缺损段神经细胞生长提供三维支架。 而且， 镁金属材料具有较好 的导电性能， 可在植入的镁合金神经导管上施加外加电场， 对神经缺损区进行电剌 激， 进一步诱导损伤区神经生长因子 （nerve growth factor, NGF) 的表达， 从而 可创造有利于神经再生的微环境， 【文献： 陈虹等， 电剌激对大鼠脊髓损伤后神经 生长因子表达的影响， 中国康复理论与实践， 2012， Vol l8， No. 1， pp. 33-36】。 此外， 镁合金降解会在人体局部区域内造成微偏碱性环境， 会有效抑制细菌生长， 达到抗 菌消炎的目的。 而高分子聚乳酸类材料降解时通常会造成局部偏酸性环境， 不利于 抗菌消炎。 以上这些都是目前临床上用于神经缺损修复的非金属类材料 （高分子聚 合物， 天然生物材料） 不具有的显著性优点。 由上可见， 可降解金属镁基导管是极 具临床应用前景的神经导管材料。
基于这些优点， 本发明首次提出应用可降解金属镁基导管作为神经导管用于周 围神经缺损的修复， 探索组织工程化人工神经修复的新途径。 针对现有技术中的缺陷，本发明的目的是提供一种用于神经缺损修复的可降解镁 合金神经导管及其制备方法。
本发明是通过以下技术方案实现的：
第一方面， 本发明提供一种用于神经缺损修复的可降解镁合金神经导管， 所述神 经导管为圆管型， 所述神经导管的管壁上设置有多列通孔， 每列通孔沿圆管轴向等 间距排布， 相邻列的通孔错位排列。
优选地， 所述神经导管的长度为 5〜50mm， 所述神经导管的厚度为 0. 1〜0. 2mm。 优选地， 所述神经导管的孔隙率为 2%〜20%， 所述通孔的孔径为 0. 1〜0. 3讓。
第二方面， 本发明还涉及前述的用于神经缺损修复的可降解镁合金神经导管的制备 方法， 所述方法包括如下步骤：
步骤 1， 将镁合金管坯一端加工出 45 ° 的锥面， 进行挤压， 得镁合金中间管材； 步骤 2， 将镁合金中间管材经多道次轧制、 拉拔后， 得毛细管；
步骤 3， 将毛细管进行去应力退火， 保温， 激光切割， 打孔， 得多孔导管； 步骤 4， 将多孔导管在超声清洗机中酸洗， 电化学抛光处理， 即得用于神经缺损修 复的可降解镁合金神经导管。
优选地， 步骤 1中， 所述镁合金管坯外径为 02Omm， 所述挤压温度为 300〜400 °C， 所述镁合金中间管材的外径为 06〜08讓， 壁厚为 0. 5〜1讓， 挤压前在模具和镁合金管 坯内、 外壁上喷涂氮化硼喷雾剂作为润滑剂。
优选地， 步骤 2中， 所述毛细管的外径为 l〜3mm， 壁厚为 0. 1〜0. 2mm。
优选地， 步骤 3中，所述去应力退火的温度为 300〜350 °C，所述保温的时间为 20〜
30 min。 优选地， 步骤 4中， 所述酸洗具体为： 在酸洗液中超声酸洗 5〜30 min。
优选地， 所述酸洗液包括如下含量的各组分： 磷酸 80〜100 ml/L， 氟化氢铵 40〜60 g/L, 溶剂为去离子水。
优选地， 步骤 4中， 所述电化学抛光处理所用的抛光液为磷酸： 无水乙醇为 1 : 1或 乙二醇乙醚：盐酸为 9 : 1，所述抛光处理的电压为 2〜8 V，抛光处理的时间为 20〜240s， 抛光处理的温度为室温。
与现有技术相比， 本发明具有如下的有益效果：
( 1 )本发明制备方法工艺简单，制备出的用于神经缺损修复的可降解镁合金神经导 管壁厚均匀、 表面光滑。
( 2 )本发明用于神经缺损修复的可降解镁合金神经导管的材质生物相容性优良，管 腔支撑效果好， 带孔管壁通透性良好， 有利于神经轴突的再生， 本发明采用多孔可降解 镁合金神经导管构建的组织工程化人工神经修复系统来桥接修复神经缺损。
( 3 )本发明采用的镁金属材料具有较好的导电性能，可在植入的镁合金神经导管上 施加外加电场， 对神经缺损区进行电剌激， 进一步诱导损伤区神经生长因子 （nerve growth factor, NGF) 的表达， 从而可创造有利于神经再生的微环境。
( 4)本发明采用的镁合金材料降解会在人体局部微区域内造成弱碱性环境，有益于 抑制细菌生长， 在手术后一定时间内可达到抗菌消炎的目的。
( 5 )本发明用于神经缺损修复的可降解镁合金神经导管的管壁均匀分布一定数量的 孔， 有利于缺损的周围神经与管壁外周围组织的营养交换， 同时导管壁分布一定数量的 孔还起到调控降解速率的作用， 有利于实现神经再生所需时间和导管降解时间的匹配。
( 6 )本发明用于神经缺损修复的可降解镁合金神经导管采用具有适宜的强韧性可降 解镁合金材质， 可满足足够的管壁支撑强度防止塌陷。
附图说明 通过阅读参照以下附图对非限制性实施例所作的详细描述， 本发明的其它特 征、 目的和优点将会变得更明显：
图 1为本发明中用于神经缺损修复的可降解镁合金神经导管 3D效果图； 图 2为本发明中用于神经缺损修复的可降解镁合金神经导管植入成年 SD大鼠坐 骨神经 6mm缺损处手术示意图；
图 3为本发明中用于神经缺损修复的可降解镁合金神经导管植入成年 SD大鼠坐 骨神经缺损处 2个月后的示意图； 图 4为大鼠足趾照片； 其中， a为实验侧； b为健侧；
图 5为再生神经横断面及纵断面组织学 HE染色图， 其中左图为再生神经横断 面 HE染色图， 右图为纵断面组织学 HE染色图。
具体实施方式
下面结合具体实施例对本发明进行详细说明。 以下实施例将有助于本领域的技术人 员进一步理解本发明， 但不以任何形式限制本发明。 应当指出的是， 对本领域的普通技 术人员来说， 在不脱离本发明构思的前提下， 还可以做出若干变形和改进。 这些都属于 本发明的保护范围。
实施例 1
本实施例涉及一种用于神经缺损修复的可降解镁合金神经导管， 其结构如图 1 所 示， 长度为 6讓， 外径为 2讓， 壁厚为 0. 2讓的圆管型， 所述神经导管的管壁上设置 有 4列通孔， 每列通孔沿圆管轴向等间距排布， 相邻列的通孔错位排列， 每列通孔 的数量为 6个， 孔径均为 0. 3讓。
本实施例涉及前述的用于神经缺损修复的可降解镁合金神经导管的制备方法， 所 示方法包括如下步骤：
步骤 1， 将外径为 20 mm的 Mg-Nd-Zn-Zr镁合金管坯一端加工出 45 ° 的锥面， 在温 度为 400 °C条件下进行挤压， 得镁合金中间管材 08x0. 5mm (外径 X壁厚）；
步骤 2， 将镁合金中间管材经多道次轧制、 拉拔后， 得外径为 2mm， 壁厚为 0. 2mm 的毛细管；
步骤 3， 将毛细管在温度为 300 °C条件下进行去应力退火， 保温 30min， 激光切割， 打孔， 得多孔导管；
步骤 4， 将多孔导管在超声清洗机中酸洗 5〜30 min (酸洗液包括如下含量的各组 分： 磷酸 80〜100 ml/L， 氟化氢铵 40〜60 g/L， 溶剂为去离子水。）， 电化学抛光处理 (采用抛光液为磷酸： 无水乙醇体积比为 1 : 1 ) 所述抛光处理的电压为 2〜8 V， 抛光处 理的时间为 20〜240s， 室温进行， 即可得用于神经缺损修复的可降解镁合金神经导管。
实施例 2
本实施例涉及一种用于神经缺损修复的可降解镁合金神经导管， 其结构如图 1 所 示， 长度为 50讓， 壁厚为 0. 15mm, 外径为 3讓的圆管型， 所述神经导管的管壁上设 置有 8列通孔， 每列通孔沿圆管轴向等间距排布， 相邻列的通孔错位排列， 每列通 孔的数量为 50个， 孔径均为 0. 03mm。 本实施例涉及前述的用于神经缺损修复的可降解镁合金神经导管的制备方法， 所 示方法包括如下步骤：
步骤 1， 将外径为 20 mm的 Mg-Zn-Zr镁合金管坯一端加工出 45 ° 的锥面， 在温度为 300 °C条件下进行挤压， 得镁合金中间管材 07x0. 8mm (外径 X壁厚）；
步骤 2， 将镁合金中间管材经多道次轧制、 拉拔后， 得外径为 3mm， 壁厚为 0. 15mm 的毛细管；
步骤 3， 将毛细管在温度为 350 °C条件下进行去应力退火， 保温 20min， 激光切割， 打孔， 得多孔导管；
步骤 4， 将多孔导管在超声清洗机中酸洗 5〜30 min (酸洗液包括如下含量的各组 分： 磷酸 80〜100 ml/L， 氟化氢铵 40〜60 g/L， 溶剂为去离子水。）， 电化学抛光处理 (采用抛光液为乙二醇乙醚： 盐酸体积比为 9 : 1 ) 所述抛光处理的电压为 2〜8 V， 抛光 处理的时间为 20〜240s，室温进行，即可得用于神经缺损修复的可降解镁合金神经导管。
实施例 3
本实施例涉及一种用于神经缺损修复的可降解镁合金神经导管， 其结构如图 1 所 示， 长度为 5讓， 壁厚为 0. 10讓， 外径为 1讓的圆管型， 所述神经导管的管壁上设置 有 4列通孔， 每列通孔沿圆管轴向等间距排布， 相邻列的通孔错位排列， 每列通孔 的数量为 5个， 孔径均为 0. 2讓。
本实施例涉及前述的用于神经缺损修复的可降解镁合金神经导管的制备方法， 所 示方法包括如下步骤：
步骤 1， 将外径为 20 mm的 Mg-Zn-Mn镁合金管坯一端加工出 45 ° 的锥面， 在温度为 320 °C条件下进行挤压， 得镁合金中间管材 06xlmm (外径 X壁厚）；
步骤 2， 将镁合金中间管材经多道次轧制、 拉拔后， 得外径为 lmm， 壁厚为 0. 10mm 的毛细管；
步骤 3， 将毛细管在温度为 300 °C条件下进行去应力退火， 保温 25min， 激光切割， 打孔， 得多孔导管；
步骤 4， 将多孔导管在超声清洗机中酸洗 5〜30 min (酸洗液包括如下含量的各组 分： 磷酸 80〜100 ml/L， 氟化氢铵 40〜60 g/L， 溶剂为去离子水。）， 电化学抛光处理 (采用抛光液为磷酸： 无水乙醇体积比为 1 : 1 ) 所述抛光处理的电压为 2〜8 V， 抛光处 理的时间为 20〜240s， 室温进行， 即可得用于神经缺损修复的可降解镁合金神经导管。 实施效果：将实施例 1〜3制得的多孔可降解镁合金神经导管分别植入到成年 SD大鼠 的坐骨神经缺损处， 手术即刻见附图 2所示。 神经导管植入大鼠体内两个月后， 大体观 察吻合口处神经再生良好， 周围未见瘢痕组织及炎症反应， 未见气泡形成， 虽然导管未 完全降解， 但是导管软化， 证实再生轴突通过导管， 达到神经修复目的， 见附图 3所示。 如附图 4所示是大鼠足趾照片 （左侧为实验侧， 右侧为健侧）， 溃疡已愈合， 与健侧比无 明显差异。 间接证实神经轴突再生良好， 神经缺损已修复。 再生神经横断面及纵断面组 织学 HE染色 （附图 5 ) 证实导管管腔内有再生的神经组织， 神经组织通过吻合口从近端 长入远端， 修复缺损。
以上对本发明的具体实施例进行了描述。 需要理解的是， 本发明并不局限于上 述特定实施方式， 本领域技术人员可以在权利要求的范围内做出各种变形或修改， 这并不影响本发明的实质内容。

Claims

权 利 要 求 书
1、 一种用于神经缺损修复的可降解镁合金神经导管， 其特征在于， 所述神经导管为 圆管型， 所述神经导管的管壁上设置有多列通孔， 每列通孔沿圆管轴向等间距排布， 相 邻列的通孔错位排列。
2、 如权利要求 1所述的用于神经缺损修复的可降解镁合金神经导管， 其特征在于， 所述神经导管的长度为 5〜50mm， 所述神经导管的厚度为 0. 1〜0. 2mm。
3、 如权利要求 1所述的用于神经缺损修复的可降解镁合金神经导管， 其特征在于， 所述通孔的孔径为 0. 03〜0. 3mm, 所述神经导管的孔隙率为 2〜20%。
4、 一种如权利要求 1 所述的用于神经缺损修复的可降解镁合金神经导管的制备方 法， 其特征在于， 所述方法包括如下步骤：
步骤 1， 将镁合金管坯一端加工出 45 ° 的锥面， 进行挤压， 得镁合金中间管材； 步骤 2， 将镁合金中间管材经多道次轧制、 拉拔后， 得毛细管；
步骤 3， 将毛细管进行去应力退火， 保温， 激光切割， 打孔， 得多孔导管； 步骤 4， 将多孔导管在超声清洗机中酸洗， 电化学抛光处理， 即可得用于神经缺损 修复的可降解镁合金神经导管。
5、如权利要求 4所述的用于神经缺损修复的可降解镁合金神经导管的制备方法，其 特征在于， 步骤 1中， 所述镁合金管坯外径为 020讓， 所述挤压温度为 300〜400 °C， 所述镁合金中间管材的外径为 06〜08mm， 壁厚为 0. 5〜lmm。
6、如权利要求 4所述的用于神经缺损修复的可降解镁合金神经导管的制备方法，其 特征在于， 步骤 2中， 所述毛细管的外径为 l〜3mm， 壁厚为 0. 1〜0. 2讓。
7、如权利要求 4所述的用于神经缺损修复的可降解镁合金神经导管的制备方法，其 特征在于， 步骤 3中， 所述去应力退火的温度为 300〜350 °C， 所述保温的时间为 20〜 30 min。
8、如权利要求 4所述的用于神经缺损修复的可降解镁合金神经导管的制备方法，其 特征在于， 步骤 4中， 所述酸洗具体为： 在酸洗液中超声酸洗 5〜30 min。
9、如权利要求 8所述的用于神经缺损修复的可降解镁合金神经导管的制备方法，其 特征在于，所述酸洗液包括如下含量的各组分：磷酸 80〜100 ml/L,氟化氢铵 40〜60 g/L， 溶剂为去离子水。
10、 如权利要求 4所述的用于神经缺损修复的可降解镁合金神经导管的制备方法， 其特征在于， 步骤 4中， 所述电化学抛光处理所用的抛光液为磷酸： 无水乙醇体积比为 1:1或乙二醇乙醚： 盐酸体积比为 9:1， 所述抛光处理的电压为 2〜8 V， 抛光处理的时 间为 20〜240s， 抛光处理的温度为室温。
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CN103598927A (zh) * 2013-10-17 2014-02-26 上海交通大学 用于神经缺损修复的可降解镁合金神经导管及其制备方法

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