阅读说明：本技术 一种Zn-Ga系合金及其制备方法与应用 (Zn-Ga alloy, preparation method and application thereof ) 是由 李华芳 郑宜星 王鲁宁 于 2020-08-03 设计创作，主要内容包括：本发明公开了一种Zn-Ga系合金及其制备方法与应用,属于医用合金技术领域,所述Zn-Ga系合金包括Zn和Ga,所述Zn-Ga系合金中Ga占0～30wt％,但不包括0,所述制备方法为将Zn和Ga或Zn、Ga和微量元素混合,进行熔炼或烧结或者熔炼或烧结之后涂覆涂层得到Zn-Ga系合金。制备的Zn-Ga系合金的力学性质符合医用植入体材料的强度和韧性的要求,同时又可体内降解,具有可生物腐蚀降解特性和适宜的腐蚀速率保证提供长期有效的力学支撑双重特性。(The invention discloses a Zn-Ga alloy and a preparation method and application thereof, belonging to the technical field of medical alloys, wherein the Zn-Ga alloy comprises Zn and Ga, the Ga in the Zn-Ga alloy accounts for 0-30 wt% but does not account for 0, and the preparation method comprises the steps of mixing Zn and Ga or Zn, Ga and trace elements, and carrying out smelting or sintering or coating after smelting or sintering to obtain the Zn-Ga alloy. The mechanical property of the prepared Zn-Ga alloy meets the requirements of strength and toughness of medical implant materials, and meanwhile, the Zn-Ga alloy can be degraded in vivo and has the dual characteristics of biological corrosion degradation and appropriate corrosion rate to guarantee the provision of long-term effective mechanical support.)

1. A Zn-Ga alloy comprising Zn and Ga, wherein Ga is 0 to 30 wt% but not 0.

2. The Zn-Ga based alloy according to claim 1, further comprising a trace element that is at least one of magnesium, calcium, strontium, manganese, titanium, zirconium, germanium, copper, silicon, phosphorus, lithium, silver, tin, and a rare earth element.

3. The Zn-Ga alloy according to claim 2, wherein the trace element accounts for 0 to 10 wt%.

4. The Zn-Ga system alloy according to claim 1, wherein a surface of the Zn-Ga system alloy is further coated with a degradable polymer coating, a degradable ceramic coating or a degradable drug coating.

5. The Zn-Ga-based alloy according to claim 1, wherein the degradable polymer coating is prepared from at least one of the following materials 1) and 2):

1) any one of polycaprolactone, polylactic acid, polyglycolic acid, L-polylactic acid, polycyanoacrylate, polyanhydride, polyphosphazene, polydioxanone, poly-hydroxybutyrate, and polyhydroxyvalerate;

2) a copolymer of any two or more of polylactic acid, polycaprolactone, polyglycolic acid, L-polylactic acid, polycyanoacrylate and polydioxanone;

the preparation material of the ceramic coating is at least one of hydroxyapatite, tricalcium phosphate or tetracalcium phosphate;

the drug coating is at least one of rapamycin and derivative coating, paclitaxel coating, everolimus coating, sirolimus coating, mitomycin coating and antibacterial coating.

6. A method for producing the Zn-Ga-based alloy according to any one of claims 1 to 5, comprising the steps of:

mixing Zn, Ga and the trace elements according to any one mode of the following 1) and 2) to obtain a mixture:

1) zn and Ga;

2) zn, Ga and trace elements;

obtaining the zinc alloy according to the following steps a) or b):

a) in CO₂And SF₆Under the protection of atmosphere, smelting or sintering the mixture, and cooling to obtain the zinc alloy;

b) in CO₂And SF₆Under the protection of atmosphere, the mixture is smelted orSintering, and coating the degradable polymer coating, the degradable ceramic coating or the degradable drug coating after cooling to obtain the Zn-Ga alloy.

7. The method according to claim 6, further comprising a step of machining the Zn-Ga alloy.

8. The method of producing a Zn-Ga based alloy according to claim 7, wherein the machining is at least one of rolling, forging, rapid solidification, and extrusion.

9. The method according to claim 6, wherein the sintering is performed by any one of the following methods: element powder mixed sintering method, pre-alloy powder sintering method and self-propagating high-temperature synthesis method.

10. Use of a Zn-Ga-based alloy according to any one of claims 1 to 5 in the preparation of a body fluid degradable medical implant.

Technical Field

The invention relates to the technical field of medical alloys, in particular to a Zn-Ga alloy and a preparation method and application thereof.

Background

The biomedical materials currently used in clinic mainly include biomedical metal materials, inorganic materials, high polymer materials, composite materials, bionic materials and the like. Compared with high molecular materials and ceramic materials, the medical metal material has higher strength, toughness and processability, so the medical metal material is most widely applied. Such as: 316L, 317L, 304V stainless steel, Co-Cr-Mo alloy, pure titanium, Ti-6Al-4V, TiNi alloy, and the like. These materials are not degradable in the human body and are permanently implanted, and when the service period of the implant in the human body is expired, the implant must be taken out through a secondary operation, thereby bringing unnecessary physiological pain and economic burden to the patient.

With the development of medical science and material science, for some materials which need temporary service, such as suture, fracture fixation plate, vascular stent, biliary stent, etc., it is desired that the material implanted into the body only plays a role of temporary substitution, and gradually degrades and absorbs along with the regeneration of tissues or organs, so as to reduce the long-term influence of the material on the body to the utmost extent. Since the biodegradable material is easily degraded by interaction with body fluid and other media in vivo, and the decomposition product can be metabolized and finally discharged out of the body without secondary operation, so that the biodegradable material is more and more emphasized by people and becomes the leading edge and research hotspot of the current international biomaterial field.

The biodegradable materials commonly used in clinic at present are mainly biodegradable high polymer materials and biodegradable ceramics. Although the biodegradable high polymer material can be completely absorbed by human bodies, the strength is low, and the function of structural support is difficult to provide; the biodegradable ceramics have the disadvantages of poor toughness and no harmonious deformation.

In recent years, degradable biomedical magnesium alloy materials become one of research hotspots, a series of biomedical degradable magnesium alloys are developed, such as AZ31, WE43, Mg-Ca and the like, although magnesium alloys have attractive application prospects as biomaterials, researches show that the magnesium alloys have too high corrosion speed, and implants can quickly lose mechanical integrity before tissues and organs are not fully healed, so that a novel degradable alloy needs to be developed to meet clinical requirements.

As with magnesium and magnesium alloys, metallic zinc and its alloys are often used as sacrificial anode materials in corrosion protection due to their chemical reactivity and susceptibility to corrosion. However, compared with magnesium, the metal zinc and the alloy thereof have higher corrosion potential, so compared with magnesium alloy, the metal zinc and the alloy thereof have slower corrosion rate, thereby being more in line with clinical requirements and being expected to be developed into novel biomedical degradable implant materials and devices.

The normal zinc content of human body is 2-3 g. Zinc is a major component of tens of enzymes in the body. Zinc is distributed in most organs and tissues, and the content of zinc in liver, muscle and bone is high. Zinc is a trace element in human body, but has a very large effect. There is a name of "life spark plug". (1) Zinc is involved in various bone matrix synthases, which are involved in bone formation and bone remodeling. When zinc is deficient, the activity of various zinc-containing enzymes in the bone is reduced, and the growth of the bone is inhibited; (2) zinc is a key component of biological membranes, which plays an important role in maintaining the structure and function of more than 2000 transcription factors and more than 300 enzymes; (3) the zinc can rapidly enter endothelial cells, maintain the integrity of the endothelial cells and reduce the susceptibility of blood vessels to atherosclerosis; (4) zinc can protect myocardial cells from acute oxidative stress and inflammatory reactions caused by myocardial injury; (5) the zinc can actively participate in nucleic acid protein synthesis to accelerate wound healing; (6) in addition, zinc is closely related to various cellular metabolism effects in vivo, such as sugar metabolism, lipid metabolism, aging resistance, and the like. Zinc deficiency can lead to arteriosclerosis, arrhythmia and failure, brain dysfunction, hypoimmunity, diarrhea, anorexia, slow growth, hair loss, night blindness, prostatic hyperplasia, male reproductive hypofunction, anemia, etc. Adult needs 15-25mg zinc per day.

Gallium (Ga) is a human bone-strengthening calcium-fixing agent, and can be used for treating cancer-related hypercalcemia and osteitis deformans. Gallium has a strong bactericidal effect because it binds to bacterial proteins. Gallium and its compound have antiinflammatory and osteoporosis resisting effects. Gallium can inhibit osteoclast resorption, inhibit osteolysis, prevent bone calcium release, change gene expression of type I collagen and fibrin in bone, is beneficial for new bone formation, can increase calcium and phosphorus content in bone, and can directly act on human bone formation.

At present, no literature and patent reports about the synthesis and performance of Zn-Ga alloy at home and abroad, and no related literature and patent proposes that Zn-Ga alloy is used as a degradable biomedical material.

Disclosure of Invention

The invention aims to provide a Zn-Ga series zinc alloy and a preparation method and application thereof, and particularly relates to the Zn-Ga series zinc alloy and the preparation method and the application thereof in preparing a medical implant capable of being degraded by body fluid. The zinc alloy prepared by the invention has excellent mechanical property, can provide long-term effective supporting force in vivo, has excellent cell compatibility, blood compatibility and tissue and organ compatibility, and can be used for biomedical implant materials.

In order to achieve the purpose, the invention provides the following scheme:

the present invention provides a Zn-Ga alloy comprising Zn and Ga, wherein Ga in the Zn-Ga alloy is 0 to 30 wt%, but not 0.

As a further improvement of the invention, the Zn-Ga alloy also comprises trace elements, wherein the trace elements are at least one of magnesium, calcium, strontium, manganese, titanium, zirconium, germanium, copper, silicon, phosphorus, lithium, silver, tin and rare earth elements, and the content of the trace elements is 0-10 wt%.

As a further improvement of the invention, the surface of the Zn-Ga system alloy is also coated with a degradable high molecular coating, a degradable ceramic coating or a degradable drug coating.

As a further improvement of the invention, the thicknesses of the degradable high-molecular coating, the degradable ceramic coating and the degradable drug coating are all 0.001-5 mm.

As a further improvement of the invention, the preparation material of the degradable high molecular coating is at least one of the following 1) and 2):

1) any one of Polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA), L-polylactic acid (PLLA), Polycyanoacrylate (PACA), polyanhydride, polyphosphazene, polydioxanone, poly-hydroxybutyrate, and polyhydroxyvalerate;

2) a copolymer of any two or more of polylactic acid (PLA), Polycaprolactone (PCL), polyglycolic acid (PGA), L-polylactic acid (PLLA), Polycyanoacrylate (PACA), and polydioxanone;

the preparation material of the degradable ceramic coating is at least one of hydroxyapatite, tricalcium phosphate or tetracalcium phosphate;

the degradable drug coating is at least one of rapamycin and derivative coatings thereof, paclitaxel coatings, everolimus coatings, sirolimus coatings, mitomycin coatings and antibacterial coatings.

As a further improvement of the invention, the Zn — Ga based zinc alloy is specifically any one of the following 1) to 4) in percentage by mass:

1) consists of 95-99% of Zn and 1-5% of Ga;

2) consists of 99% Zn and 1% Ga;

3) consists of 98% Zn and 2% Ga;

4) consists of 98.5% Zn, 1% Ga and 0.5% Y.

The Zn-Ga series zinc alloy prepared by the invention has a compact structure or a porous structure, has good histocompatibility, and is a reliable biomedical implant material.

The invention also provides a preparation method of the Zn-Ga alloy, which comprises the following steps:

mixing Zn, Ga and the trace elements according to any one mode of the following 1) and 2) to obtain a mixture:

1) zn and Ga;

2) zn, Ga and trace elements;

obtaining the zinc alloy according to the following steps a) or b):

a) in CO₂And SF₆Under the protection of atmosphere, smelting or sintering the mixture, and cooling to obtain the zinc alloy;

b) in CO₂And SF₆And under the protection of atmosphere, smelting or sintering the mixture, cooling and coating the degradable high polymer coating, the degradable ceramic coating or the degradable drug coating to obtain the zinc alloy. The method for preparing the zinc alloy also comprises the step of coating so as to meet different clinical requirements.

As a further improvement of the method, the smelting temperature in the preparation method is 500-700 ℃.

As a further improvement of the invention, the preparation method also comprises the step of machining the zinc alloy.

As a further improvement of the present invention, the machining is at least one of rolling, forging, rapid solidification, and extrusion.

As a further improvement of the invention, the rolling is repeated in a reversing mill at a hot rolling temperature of 250 ℃ and finally in a finishing mill at 250 ℃ to a thickness of 1.5 mm.

As a further improvement of the invention, the forging comprises the steps of carrying out heat preservation on the Zn-Ga alloy at the temperature of 150-200 ℃ and carrying out forging at the temperature of 200-300 ℃, wherein the heat preservation time is 3-50 h, and the forging speed is not less than 350 mm/s.

As a further improvement of the invention, the extrusion temperature is 150-250 ℃, specifically 200-220 ℃; the extrusion ratio is 10-70, specifically 20-25.

As a further improvement of the present invention, the rapid solidification comprises the steps of: under the protection of Ar gas, a high-vacuum rapid quenching system is adopted to prepare a rapid solidification thin strip, then the thin strip is crushed into powder, and then the vacuum hot pressing is carried out for 1-24 hours at the temperature of 200-350 ℃.

As a further improvement of the invention, the high vacuum rapid quenching system is arranged as follows: the feeding amount is 2-8 g, the induction heating power is 3-7 kW, the distance between a nozzle and a roller is 0.80mm, the injection pressure is 0.05-0.2 MPa, the rotating speed of a roller is 500-3000 r/min, and the slit size of the nozzle is 1film multiplied by 8mm multiplied by 6 mm.

As a further improvement of the present invention, the sintering is any one of the following methods: element powder mixed sintering method, pre-alloy powder sintering method and self-propagating high-temperature synthesis method.

As a further improvement of the invention, the element powder mixed sintering method is that the raw materials for preparing the porous structure Zn-Ga series alloy are uniformly mixed, pressed into a blank, then slowly heated to 100-200 ℃ at a speed of 2-4 ℃/min in a vacuum sintering furnace, then rapidly heated to 200-300 ℃ at a speed of 30 ℃/min for sintering, and then cooled to obtain the porous structure Zn-Ga series alloy;

as a further improvement of the invention, the pre-alloy powder sintering method is that the raw materials for preparing the porous Zn-Ga alloy are mixed and subjected to high-energy ball milling, then the mixture is pressed and formed, and the heat treatment is carried out at 250-350 ℃ for 10-20 hours to obtain the porous Zn-Ga alloy;

as a further improvement of the invention, the self-propagating high-temperature synthesis method is to mix raw materials for preparing the Zn-Ga alloy with the porous structure and press the mixture into a blank, and the pressure is 1 × 10 under the protection of inert gas³～1×10⁵Pa at the temperature of 250-350 ℃, and then igniting the Zn-Ga alloy blank to carry out self-propagating high-temperature synthesis to obtain the Zn-Ga alloy with the porous structure.

As a further improvement of the invention, the method for coating the biodegradable polymer coating is to carry out acid cleaning on the zinc alloy, then dip-coat the zinc alloy in colloid prepared by dissolving the preparation material of the biodegradable polymer coating in trichloroethane for 10-30 min, pull out at a constant speed and carry out centrifugal treatment to obtain the zinc alloy coated with the biodegradable polymer coating.

As a further improvement of the present invention, the method for applying the degradable ceramic coating may be any one of plasma spraying, electrophoretic deposition, anodic oxidation and hydrothermal synthesis;

as a further improvement of the invention, the main plasma gas used for plasma spraying is Ar, the flow rate is 30-100 scfh, and the secondary plasma gas is H₂The flow is 5-20 scfh, the spraying current is 400-800A, the spraying voltage is 40-80V, and the spraying distance is 100-500 mm;

as a further improvement of the invention, the method for electrodepositing the degradable ceramic coating is to use zinc alloy as a cathode in electrolyte containing calcium and phosphate, and the current density is 2-10 mA/cm²After 10-60 min of treatment, cleaning and drying to obtain the zinc alloy;

as a further improvement of the invention, the method combining anodic oxidation and hydrothermal synthesis comprises the steps of oxidizing the zinc alloy in an electrolyte containing 0.01-0.5 mol/L beta-sodium glycerophosphate and 0.1-2 mol/L calcium acetate at 200-500V for 10-30 min, and then treating the zinc alloy at 200-400 ℃ for 1-4 h.

As a further improvement of the invention, the method for coating the degradable drug coating is a physical and chemical method;

the physical method coating process mainly adopts a soaking and spraying method; the chemical method mainly applies the electrochemical principle to carry out electroplating;

the soaking method is that active medicine and controlled release carrier (or single active medicine) are prepared into solution, the specific concentration can be different due to different solution viscosity and required medicine dosage, then the medical implant is soaked into the solution, and then the medicine coating is prepared through necessary post-treatment processes, such as cross-linking, drying, curing and other steps;

the spraying method is that the active drug and the controlled release carrier (or the single active drug) are prepared into solution, then the solution is evenly coated on the surface of the medical implant through a spraying tool or a special spraying device, and the drug coating is prepared after post-treatment steps such as drying, curing and the like;

the chemical method is that active medicine and/or controlled release carrier are used to generate electric oxidation reduction reaction on the electrode made by the medical implantation, so that the medical implantation surface forms a stable medicine coating connected by chemical bonds.

The invention utilizes the characteristic that Zn and Zn alloy are easy to corrode, and selects Zn-Ga alloy as a degradable material to be applied to the medical implant. The Zn-Ga alloy has mechanical property meeting the requirement of medical implant material on strength and toughness, and is degradable in vivo, so that the defect that medical polymer material has low strength and traditional medical metal materials such as 316L stainless steel, titanium alloy and the like are not degradable can be overcome, the defect that the mechanical property in the implant is lost due to too high degradation rate of magnesium and magnesium alloy can be overcome, and the Zn-Ga alloy has the dual characteristics of 'biological corrosion degradation characteristic' and 'proper corrosion rate' to ensure that long-term effective mechanical support is provided.

The invention also provides application of the Zn-Ga alloy, and the Zn-Ga alloy is used for preparing the medical implant capable of being degraded by body fluid. The body fluid degradable medical implant comprises: an implantation stent, a bone repair instrument and a craniomaxillofacial repair instrument for treatment;

as a further improvement of the invention, the therapeutic implant stent can be a vascular stent, an esophageal stent, an intestinal stent, a tracheal stent, a biliary stent or a urethral stent;

the bone repair apparatus can be a bone tissue repair bracket, an osteosynthesis device, a fixing wire, a fixing screw, a fixing rivet, a fixing needle, a bone clamping plate, an intramedullary needle or a bone sleeve;

the craniomaxillofacial restoration apparatus can be a craniofacial restoration net, a maxillofacial bone defect restoration bracket and the like.

The invention discloses the following technical effects:

(1) the mechanical property of the Zn-Ga alloy prepared by the invention meets the requirements of strength and toughness of medical implant materials, and simultaneously, the Zn-Ga alloy can be degraded in vivo and has the dual characteristics of 'biological corrosion degradation characteristic' and 'proper corrosion rate guarantee to provide long-term effective mechanical support'.

(2) When the Zn-Ga alloy is used for degradable medical implants, the Zn-Ga alloy can not only exert the high strength characteristic of the metal material of the degradable medical implants within a period of time after being implanted to complete the functions of the implants (such as inducing new bone tissues to form or supporting narrow blood vessels), but also be used as a variant body to be gradually corroded and degraded by a human body while being used for self-repairing the pathological change parts of the human body, the quantity and the volume are gradually reduced, the dissolved metal ions can be absorbed and utilized by organisms to promote the growth of bones or metabolism to be discharged out of the body, and finally the metal material implants are completely degraded and disappear when the human body finishes self-repairing.

(3) The medical implant capable of being degraded by body fluid is non-toxic and has good histocompatibility and blood compatibility.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings without inventive exercise.

FIG. 1 shows the result of cytocompatibility test of cells in Zn-Ga alloy.

Detailed Description

Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.

It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The specification and examples are exemplary only.

As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.

The percentages used in the following examples are by weight unless otherwise specified.