WO2017028646A1 - 生物可降解的医用锌铜合金及其制备方法和用途 - Google Patents

生物可降解的医用锌铜合金及其制备方法和用途 Download PDF

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WO2017028646A1
WO2017028646A1 PCT/CN2016/089732 CN2016089732W WO2017028646A1 WO 2017028646 A1 WO2017028646 A1 WO 2017028646A1 CN 2016089732 W CN2016089732 W CN 2016089732W WO 2017028646 A1 WO2017028646 A1 WO 2017028646A1
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zinc
copper
copper alloy
alloy
biodegradable medical
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French (fr)
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黄华
袁广银
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Shanghai Jiao Tong University
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    • C—CHEMISTRY; METALLURGY
    • C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
    • C22C—ALLOYS
    • C22C18/00—Alloys based on zinc
    • C22C18/02—Alloys based on zinc with copper as the next major constituent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws or setting implements
    • A61B17/68—Internal fixation devices, including fasteners and spinal fixators, even if a part thereof projects from the skin
    • A61B17/80—Cortical plates, i.e. bone plates; Instruments for holding or positioning cortical plates, or for compressing bones attached to cortical plates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws or setting implements
    • A61B17/68—Internal fixation devices, including fasteners and spinal fixators, even if a part thereof projects from the skin
    • A61B17/84—Fasteners therefor or fasteners being internal fixation devices
    • A61B17/86—Pins or screws or threaded wires; nuts therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • 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
    • 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
    • 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
    • A61L31/148—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
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws or setting implements
    • A61B17/68—Internal fixation devices, including fasteners and spinal fixators, even if a part thereof projects from the skin
    • A61B17/84—Fasteners therefor or fasteners being internal fixation devices
    • A61B17/86—Pins or screws or threaded wires; nuts therefor
    • A61B17/866—Material or manufacture
    • 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
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the invention relates to a biodegradable medical zinc-copper alloy, a preparation method thereof and use thereof, and belongs to the technical field of medical materials.
  • medical materials implanted into the human body are generally made of non-degradable metal materials, such as austenitic stainless steel, cobalt chromium alloy, medical tantalum, titanium and its alloy, nickel-titanium shape memory alloy, platinum-iridium alloy.
  • non-degradable metal materials such as austenitic stainless steel, cobalt chromium alloy, medical tantalum, titanium and its alloy, nickel-titanium shape memory alloy, platinum-iridium alloy.
  • the permanent metal stent is not degradable after implantation in the human body, and there is a shortage of thrombus to cause restenosis in the stent and intimal fibrosis, and the stent is permanently In the body, can not be removed again, once the vascular occlusion occurs in the same position, it is very difficult to implant a vascular stent; 2, stainless steel, titanium alloy bone nails, bone plates, etc., after implantation in the human body, after the bone tissue is healed The second surgery removes it, increasing the patient's pain and financial burden. Therefore, research and development of medical metal materials with good mechanical properties and biocompatible properties in vivo degradation has become an important development direction in this field.
  • the present invention provides a biodegradable medical zinc-copper alloy composed of copper element, zinc element and unavoidable impurity element, wherein the weight percentage of copper element is 1 to 10%, which is unavoidable The weight percentage of the impurity element does not exceed 0.1%.
  • the copper element has a weight percentage of from 1 to 4%.
  • the present invention provides a method for preparing a biodegradable medical zinc-copper alloy as described above, which is obtained by smelting pure zinc and brass or copper as a raw material, and then casting a zinc-copper alloy ingot, preferably
  • the pure zinc is a zinc ingot having a purity of not less than 99.995%, the content of copper in the brass is 62% by weight, and the purity of copper in the copper is not less than 99.99%.
  • the preparation method of the biodegradable medical zinc-copper alloy specifically includes the following operations:
  • the pure zinc is heated and melted, and after the pure zinc is completely melted, brass or copper is added, and after the brass or copper is completely melted, an alloy liquid is formed;
  • the alloy liquid is stirred, slag, and left to be cast and demolded to obtain an as-cast zinc-copper alloy ingot material;
  • the as-cast zinc-copper alloy ingot material is heat-treated at 350 to 380 ° C for heat treatment, and then hot extruded, drawn or rolled at 200 to 350 ° C to obtain a zinc-copper alloy wire and a bar. Pipe or sheet.
  • the controlled extrusion ratio is 9 to 50.
  • the amount of deformation for controlling the single pass rolling is 5 to 20%.
  • the invention also provides the use of a biodegradable medical zinc-copper alloy in a medical device.
  • the medical device comprises one of a catheter-based device and an orthopedic implant-based device.
  • the catheter-based device comprises a vascular stent, a bile duct stent or a tracheal stent;
  • the orthopedic implant device comprises a bone plate or a bone nail.
  • the medical device comprises a catheter device such as a vascular stent, a bile duct stent, a tracheal stent, and an orthopedic implant device such as a bone plate or a bone nail.
  • a catheter device such as a vascular stent, a bile duct stent, a tracheal stent, and an orthopedic implant device such as a bone plate or a bone nail.
  • Zinc is a component of many proteins and nucleic acid synthetases and is the active center of hundreds of enzymes. Zinc is an insulin component and is a key factor in maintaining normal life. Zinc deficiency can cause all physiological functions of the human body to be disordered. Zinc alloys have potential applications as biodegradable medical implant materials.
  • Copper accounts for one-millionth of the body's weight, and each person contains about 100-150mg.
  • Adults must consume 3 to 5 mg of copper per day to maintain a metabolic balance.
  • the primary signs of copper deficiency in infants and girls are neutropenia, hypopigmentation anemia, ineffective treatment with iron, osteoporosis, and bone lesions that occur when vitamin C is deficient.
  • skin and hair pigmentation pale, seborrheic dermatitis, superficial vein dilatation, bad food, diarrhea, hepatosplenomegaly, growth arrest.
  • the physiological functions of copper mainly include the following aspects: To protect normal hematopoietic function, it is manifested in the following two aspects: (1) promote iron absorption and transportation; 2 ceruloplasmin can promote the synthesis of heme and hemoglobin. 2. Maintain normal bones, blood vessels and skin. The copper enzyme lysyl oxidase promotes the crosslinking of collagen, elastin in bone, blood vessels and skin. 3. Maintain the health of the central nervous system. 4. Protect the body cells from the poison of superoxide ions.
  • copper ions can induce endothelial growth factor, promote the proliferation of endothelial cells, accelerate the process of angiogenesis, but prevent the excessive proliferation of smooth muscle cells; and can inhibit the formation of thrombosis, etc., can effectively reduce the restenosis caused by vascular stents and other implants Rate (reference: GfHu. Copper enhances proliferation of human endothelial cells under culture [J]. Journal of Cellular Biochemistry. 1998, 69(3): 326-335.). 6. Copper ions can promote the formation and growth of bone tissue by promoting the deposition of collagen, which promotes osteogenesis (Reference: C. opposition, L.-J. Bordeleau, J. Barralet, CJ Doillon. The stimulation Of angiogenesis and collagen deposition by copper [J].
  • Copper ions have a bactericidal effect, which is of great value for implanting instruments.
  • Copper also affects many physiological, biochemical and pathophysiological processes such as cholesterol metabolism, myocardial oxidative metabolism, body defense function, and hormone secretion. Therefore, the copper element is selected as the main alloying element of the zinc-based alloy.
  • the strength and plasticity of zinc increase the role of strengthening and toughening materials.
  • the release of trace copper ions is The above-mentioned beneficial biological function to the human body is the innovative design idea of the biodegradable Zn-Cu binary alloy of the present invention.
  • the present invention has the following beneficial effects:
  • the zinc alloy of the invention has the advantages of good mechanical property, easy processing, excellent corrosion resistance, good biocompatibility, tensile strength of 187 to 271 MPa, tensile yield strength of 150 to 230 MPa, and elongation of 22.2. 52.3%;
  • Embodiment 1 is a metallographic microstructure diagram of four as-cast alloy ingots described in Embodiment 1;
  • Example 2 is a metallographic microstructure diagram of a Zn-Cu alloy extruded bar in Concrete Example 2.
  • a biodegradable medical Zn-Cu binary alloy material of the present invention contains (% by weight): Cu 1-4%, and zinc is the balance.
  • the material structure determines the material properties. Therefore, the structure of the alloy can be adjusted according to the application requirements. For example, the composition of the alloy is adjusted within the range of the above alloy composition content, the alloy is heat treated, and the alloy is subjected to deformation processing (such as rolling). , extrusion, etc.) to adjust the structure of the alloy to achieve the purpose of improving and improving the properties of the alloy.
  • deformation processing such as rolling
  • extrusion etc.
  • the Zn-Cu binary alloy ingot material is prepared by using the existing conventional resistance furnace alloy smelting casting process, that is, the pure zinc is melted in the electric resistance furnace, the Cu-Zn intermediate alloy is added and the temperature is raised to 550 ° C for 60 min; After complete melting, the alloy liquid is stirred, the stirring time is 10-15 min, and the slag is further slag, left standing for 10-30 min, and then cast and demolded to obtain an as-cast Zn-Cu binary alloy ingot.
  • the purity of Zn in the raw material was 99.995%, and the addition of Cu was selected from one of Cu-38 wt.% Zn binary intermediate alloy or oxygen-free copper (purity 99.99%).
  • the metallographic structure of the sample obtained after alloy casting is shown in Fig. 1.
  • the second phase of the above four Zn-Cu binary alloy materials is mainly CuZn5 (white dendritic second phase), as indicated in FIG.
  • the results of biological tests show that the above four Zn-Cu binary alloy materials have no obvious cytotoxicity and good biocompatibility.
  • the metallographic structure after hot extrusion is shown in Figure 2. After extrusion, the second phase is broken and distributed in a strip shape along the extrusion direction. After extrusion, the grain size is remarkably refined, and the grain size is between 1-10 ⁇ m.
  • Table 1 The test results of room temperature mechanical properties after extrusion are shown in Table 1.
  • the tensile strength of Zn-Cu binary alloy is in the range of 187-271MPa, the yield strength is in the range of 150-230MPa, the elongation is in the range of 20%-55%, and the corrosion rate is in the range of 0.02-0.2mm per year, which is suitable for degradation.
  • the clinical application requirements of medical materials are suitable for further preparation of degradable vascular stents, bile duct stents, tracheal stents, bone plates, bone nails, bone tissue engineering stents and the like.
  • the Zn-1Cu alloy ingot casting machine of Example 1 was processed into a sheet of 10 mm thick, and further hot rolled at 350 ° C, and the rolling amount per pass was about 10%, and finally a sheet having a thickness of about 2 mm was obtained.
  • the mechanical properties of the sheet are along the rolling direction, the tensile strength is 210 MPa, the yield strength is 160 MPa, the elongation is 19.8%, and the corrosion rate in the 37° Chanks solution is 0.18 mm/year.
  • it can be further processed into products and used to prepare degradable bone plate implant materials.
  • the Zn-2Cu extruded bar obtained in Example 2 was machined into a seamless extruded tube blank having a diameter of 20 mm and a height of 13 mm, and extruded at 300 ° C to obtain a seamless tube having an outer diameter of 8 mm and a wall thickness of 0.8 mm. . Then, the seamless pipe obtained by extrusion is subjected to room temperature rolling or room temperature drawing, and rolling or drawing is performed between the passes. Annealing treatment at 300 ° C ⁇ 30 min. The process was finally prepared to obtain a capillary material having an outer diameter of 3 mm and a wall thickness of 0.185 mm.
  • the tensile strength of the pipe was 240 MPa, the yield strength was 200 MPa, the elongation was 40.3%, and the corrosion rate in the 37° Chanks solution was 0.12 mm/year. It meets the clinical application requirements of implantable materials in degradable medical stents, and can be laser-cut to prepare vascular stents, bile duct stents, and tracheal stents.
  • the Zn-3Cu extruded extruded bar obtained in Example 2 was machined into a cylindrical ingot extrusion having a diameter of 20 mm and a height of 30 mm, and extruded at 330 ° C into a wire having a diameter of 1.5 mm.
  • the wire had a tensile strength of 270 MPa, a yield strength of 220 MPa, and an elongation of 52%.
  • the wire was subjected to multi-pass cold drawing, and the drawing was performed at 350 ° C for 30 min to obtain a fine wire having a diameter of 500 mm to 50 ⁇ m.
  • Typical mechanical properties of the microfilament tensile strength of 255 MPa, yield strength of 216 MPa, and elongation of 44.6%.
  • the corrosion degradation rate in the 37° Chanks solution was 0.08 mm/year.
  • the wire is used to prepare a degradable catheter, which can be used as a stent for implants such as a vascular stent, a bile duct stent, and a tracheal stent.

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Abstract

一种可以应用于医用植入材料的生物可降解锌铜合金材料及其制备方法和应用。该材料主要由下列物质组成：铜1～10wt.％，其余为锌和其它杂质元素。对铸态合金锭进行均匀化热处理，然后可再进行热塑性变形加工细化合金组织从而提高合金力学性能的同时可进一步制备成管材、丝材及板材等。该锌合金具有力学性能好、易加工、耐蚀性优良、生物相容性好等优点，可以作为制备多种可降解医用植入器械的材料，不仅具有非常优良的力学性能和生物相容性能，同时可以在6～18个月内实现完全降解，满足植入器械对材料综合力学性能和生物安全性的要求。

Description

生物可降解的医用锌铜合金及其制备方法和用途 技术领域
本发明涉及一种生物可降解的医用锌铜合金及其制备方法和用途，属于医用材料技术领域。
背景技术
目前，手术植入人体内的医用材料一般采用的是不可降解的金属材料，例如奥氏体不锈钢、钴铬合金、医用钽、钛及其合金、镍钛形状记忆合金、铂铱合金。这些永久性植入材料的应用存在如下弊端，例如1、永久性金属血管支架植入人体后由于其不可降解，存在着容易形成血栓造成支架内再狭窄、内膜纤维化的不足，而且支架永久存留体内，不能再次取出，一旦在同一位置再发生血管堵塞，再植入一个血管支架变得非常困难；2、不锈钢、钛合金骨钉、骨板等植入人体后，在骨组织痊愈后需要二次手术将其取出，增加了患者的痛苦和经济负担。因此研究和开发具有良好的力学性能与生物相容性能的体内降解的医用金属材料成为该领域中的重要发展方向。
发明内容
针对现有技术中的缺陷，本发明的目的是提供一种生物可降解的医用锌铜合金及其制备方法和用途。
本发明是通过以下技术方案实现的：
第一方面，本发明提供了一种生物可降解的医用锌铜合金，其由铜元素、锌元素以及不可避免的杂质元素组成，其中，铜元素的重量百分数为1～10％，不可避免的杂质元素的重量百分数不超过0.1％。
作为优选方案，所述铜元素的重量百分数为1～4％。
第二方面，本发明提供了一种如前述的生物可降解的医用锌铜合金的制备方法，是以纯锌和黄铜或紫铜为原料，进行熔炼，浇注后得到锌铜合金铸锭，优选地，纯锌为纯度不低于99.995％的锌锭，黄铜中的铜的含量为62wt％，紫铜中铜的纯度不低于99.99％。
作为优选方案，所述的生物可降解的医用锌铜合金的制备方法的具体包括如下操作：
对纯锌进行加热熔化，将所述纯锌完全熔化后，加入黄铜或紫铜，待所述黄铜或紫铜完全熔化后，形成合金液；
对所述合金液进行搅拌、扒渣、静置后进行浇注、脱模，得到铸态锌铜合金铸锭材料；
将所述铸态锌铜合金铸锭材料在350～380℃下保温进行热处理后，在200～350℃下进行热挤压，拉拔或轧制加工，得到锌铜合金丝材，棒材，管材或板材。
作为优选方案，所述热挤压的操作中，控制挤压比为9～50。
作为优选方案，所述热轧制加工中，控制单道次轧制的变形量为5～20％。
第三方面，本发明还提供了生物可降解的医用锌铜合金在医疗器械中的用途。
作为优选方案，所述医疗器械包括导管类器械、骨外科植入类器械中的一种。
作为优选方案，所述导管类器械包括血管类支架、胆管类支架或气管类支架；所述骨外科植入类器械包括骨板或骨钉。
作为优选方案，所述医疗器械包括血管类支架、胆管类支架、气管类支架等导管类器械和骨板或骨钉等骨外科植入类器械。
众所周知，铜和锌均为人体最为基本的必要微量元素。其中，锌能促进细胞的更新，可增强人体的免疫能力，维持肌体的生长和发育。锌是许多蛋白质、核酸合成酶的成分，是上百种酶的活性中心。锌又为胰岛素成分，是维持生命正常活动的关键因素。锌缺损可能导致人体所有的生理机能紊乱。锌合金作为生物可降解医用植入材料具有潜在的应用前景。
铜占人体体重的百万分之一，每人约含100～150mg。成年人每天必须摄入3～5mg铜，才能维持代谢的平衡。婴儿和女童缺铜的首要征象为中性粒细胞缺乏症，低色素性贫血，用铁治疗无效，骨质疏松，类似维生素C缺乏时所发生的骨质病变。其次为皮肤及毛发色素减少、苍白，脂溢性皮炎，浅表静脉扩张、恶食、腹泻、肝脾肿大、生长停滞。铜的生理功用主要有如下几个方面：1、维 护正常的造血机能，表现在以下两方面：①促进铁的吸收和运输；②铜蓝蛋白能促进血红素和血红蛋白的合成。2、维护骨骼、血管和皮肤的正常。铜酶赖氨酰氧化酶促进骨骼、血管和皮肤胶原和弹性蛋白的交联。3、维护中枢神经系统的健康。4、保护肌体细胞免受超氧离子的毒害。5、铜离子能够诱导内皮生长因子，促进内皮细胞的增殖，加快血管再生过程，但阻止平滑肌细胞的过度增殖；并能抑制血栓形成等功效，可有效降低血管支架等植入后引发的再狭窄率(参考文献：G.f.Hu.Copper stimulates proliferation of human endothelial cells under culture[J].Journal of Cellular Biochemistry.1998,69(3):326-335.)。6、铜离子能够通过促进骨胶原的沉积而促进骨组织的形成与生长，即具有促进成骨作用(参考文献：C.Gérard，L.-J.Bordeleau，J.Barralet，C.J.Doillon.The stimulation of angiogenesis and collagen deposition by copper[J].Biomaterials.2010,31(5):824-831.)。7、铜离子具有杀菌效果，这对于植入器械具有重要价值。8、其他：铜对胆固醇代谢、心肌细胞氧化代谢、肌体防御机能、激素分泌等许多生理、生化和病理生理过程也有影响。因此，选择铜元素为锌基合金的主要添加合金化元素，一方面增加锌的强度和塑性起到强韧化材料的作用，另一方面材料在降解的过程中，微量的铜离子的释放是对人体具有上述有益的生物功能作用，这就是本发明生物可降解Zn-Cu二元合金的创新设计思想。
与现有技术相比，本发明具有如下的有益效果：
1、本发明的锌合金具有力学性能好、易加工、耐蚀性优良、生物相容性好等优点，抗拉强度为187～271MPa，拉伸屈服强度为150～230MPa，延伸率为22.2～52.3％；
2、耐腐蚀性能优良，在37℃的Hanks溶液中的腐蚀速度为0.02～0.2毫米/年；
3、可以作为制备多种可降解医用植入器械的材料，不仅具有非常优良的力学性能和生物相容性能，同时可以在6～18个月内实现完全降解；
4、适用于制备可降解的医用植入丝材、血管支架、胆管支架、气管支架、骨板、骨钉和骨组织工程支架等，完全满足上述植入器械对材料综合力学性能和生物安全性的要求。
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为具体实施1中所述的四种铸态合金锭的金相显微组织图；
图2为具体实施例2中Zn-Cu合金挤压棒材的金相显微组织图。
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。
本发明的一种生物可降解医用Zn-Cu二元合金材料含有(重量％)：Cu1～4％，锌为余量。
材料的组织决定材料性能，因此，根据应用需要可以对合金的组织进行调控，例如，在上述的合金成分含量的范围内调整合金的成分、对合金进行热处理、对合金进行变形加工(如轧制、挤压等)等手段调整合金的组织，从而达到提高和改善合金性能的目的。
实施例1
采用现有的传统电阻炉合金熔炼铸造工艺制备得到Zn-Cu二元合金铸锭材料，即在电阻炉中将纯锌熔化，添加Cu-Zn中间合金并升温至550℃保温60min；待中间合金完全熔化后，对合金液进行搅拌，搅拌时间为10-15min，再扒渣，静置10-30min后浇注、脱模得到铸态Zn-Cu二元合金铸锭。四种代表性的Zn-xCu(x＝1,2,3,4wt.％)合金材料铸态组织如附图1所示。原料中Zn的纯度为99.995％，Cu的加入选择以Cu-38wt.％Zn二元中间合金或无氧紫铜(纯度99.99％)两种中的一种为原料。合金浇注后所得试样的金相组织如附图1所示。上述四种Zn-Cu二元合金材料中的第二相主要为CuZn5(白色的树枝状第二相)，如附图1标示。生物学试验结果表明上述四种Zn-Cu二元合金材料均无明显的细胞毒性，具有良好的生物相容性。
实施例2
对实施例1中所得的四种代表性Zn-xCu(x＝1,2,3,4)铸锭材料进行360℃-380℃保温8个小时的均匀化热处理，随后进行280℃挤压比为9:1的挤压，使其具有比较均匀的组织且晶粒细小，从而进一步改善合金的性能，并制得挤压棒材(或板材)。热挤压后的金相组织如附图2所示。挤压后第二相发生破碎并沿挤压方向呈条带状分布。挤压后晶粒尺寸得到明显细化，晶粒尺寸在1-10μm之间。挤压后的室温力学性能测试结果如附表1所示。Zn-Cu二元合金抗拉强度在187-271MPa范围内，屈服强度在150-230MPa范围内，延伸率在20％-55％范围内，腐蚀速率在0.02-0.2毫米每年范围内，满足可降解医用材料临床应用要求，适合进一步制备可降解的血管支架、胆管支架、气管支架、骨板、骨钉、骨组织工程支架等植入器械。
本实施例制备的锌铜合金铸锭材料的力学性能如表1所示。
附表1：挤压态合金的力学性能
Figure PCTCN2016089732-appb-000001
实施例3
对实施例1中的Zn-1Cu合金铸锭机加工成10mm厚的板材，再进行350℃热轧，每道次轧制量约为10％，最终得到板厚约2mm的板材。板材的力学性能为沿着轧制方向，其抗拉强度为210MPa，屈服强度为160MPa延伸率为19.8％，37℃hanks溶液中的腐蚀速率为0.18毫米/年。满足可降解医用材料临床应用要求，可进一步机加工成产品并应用于制备可降解的骨板类内植入材料。
实施例4
对实施例2中所得到的Zn-2Cu挤压棒材机加工成直径20mm高度13mm的无缝挤压管坯，在300℃挤压得到外径为8mm，壁厚为0.8mm的无缝管。再对挤压得到的无缝管进行室温轧制或者室温拉拔，轧制或拉拔道次间施以 300℃×30min的退火处理。工艺最终制备得到外径为3mm壁厚为0.185mm的毛细管材。管材的抗拉强度为240MPa，屈服强度为200MPa，延伸率为40.3％，37℃hanks溶液中的腐蚀速率为0.12毫米/年。满足可降解医用支架类内植入材料临床应用要求，可激光切割制备成血管支架、胆管支架、气管支架。
实施例5
对实施例2中所得到的Zn-3Cu挤压挤压棒材机加工成直径20mm高度30mm的圆柱锭挤压坯料，在330℃挤压成直径1.5mm的丝材。该丝材的抗拉强度为270MPa，屈服强度为220MPa，延伸率为52％。对该丝材进行多道次冷拉拔加工，拉拔道次间施以350℃×30min的退火处理，最终得到了直径为500mm至50μm的微细丝材。该微细丝材的典型力学性能：抗拉强度为255MPa，屈服强度为216MPa，延伸率为44.6％。37℃hanks溶液中的腐蚀降解速度为0.08毫米/年。采用该丝材编制出了可降解导管，可用作血管支架、胆管支架、气管支架等支架内植入器械。
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 (9)

  1. 一种生物可降解的医用锌铜合金，其特征在于，由铜元素、锌元素以及不可避免的杂质元素组成，其中，铜元素的重量百分数为1～10％，不可避免的杂质元素的重量百分数不超过0.1％。
  2. 如权利要求1所述的生物可降解的医用锌铜合金，其特征在于，所述铜元素的重量百分数为1～4％。
  3. 一种如权利要求1或2所述的生物可降解的医用锌铜合金的制备方法，其特征在于，是以纯锌和黄铜或紫铜为原料，进行熔炼，得到锌铜合金铸锭。
  4. 如权利要求3所述的生物可降解的医用锌铜合金的制备方法，其特征在于，具体包括如下操作：
    对纯锌进行加热熔化，待纯锌完全熔化后，加入黄铜或紫铜，待所述的黄铜或紫铜完全熔化后，形成合金液；
    对所述合金液进行搅拌、扒渣、静置后进行浇注、脱模，得到铸态锌铜合金铸锭材料；
    将所述铸态锌铜合金铸锭材料在350～380℃下保温进行热处理后，在200～350℃下进行热挤压，拉拔或轧制加工，得到锌铜合金丝材，棒材，管材或板材。
  5. 如权利要求4所述的生物可降解的医用锌铜合金的制备方法，其特征在于，所述热挤压的操作中，控制挤压比为9～50。
  6. 如权利要求4所述的生物可降解的医用锌铜合金的制备方法，其特征在于，所述轧制加工中，控制单道次轧制的变形量为5～20％。
  7. 一种如权利要求1或2所述的生物可降解的医用锌铜合金在医疗器械中的用途。
  8. 如权利要求7所述的用途，其特征在于，所述医疗器械包括导管类器械、骨外科植入类器械中的一种。
  9. 如权利要求8所述的用途，其特征在于，所述导管类器械包括血管类支架、胆管类支架或气管类支架；所述骨外科植入类器械包括骨板或骨钉。
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