WO2011160534A1

WO2011160534A1 - Magnesium alloy used for degradable stent material in vivo and preparation method thereof

Info

Publication number: WO2011160534A1
Application number: PCT/CN2011/074842
Authority: WO
Inventors: 袁广银; 付彭怀; 丁文江
Original assignee: 上海交通大学
Priority date: 2010-06-22
Filing date: 2011-05-30
Publication date: 2011-12-29
Also published as: CN101837145A; WO2011160533A1; CN101837145B

Abstract

Disclosed is a magnesium alloy used for degradable stent material in vivo and preparation method thereof. The components and their weight ratio of magnesium alloy are: Nd 1-2.49%, Zn 0.1-2%, Zr 0-0.6%, impurities 0-0.2% and balance Mg. The magnesium alloy has better mechanical property and plastic deformation property than WE43, desired uniform corrosion resistance and good biocompatibility. The magnesium alloy can be applied to prepare lumen support which is used for short-term intervention therapeutic of vessel, biliary duct, pancreatic duct, and esophagus and so on.

Description

In vivo degradable magnesium alloy vascular stent material and manufacturing method thereof

Technical field

The invention relates to an alloy and a preparation thereof in the technical field of biomedical materials, in particular to an in vivo degradable magnesium alloy vascular stent material and a manufacturing method thereof.

Background technique

In the field of cardiovascular disease treatment, interventional stenting has become the most important means. However, the current clinical application of cardiovascular stents is still based on non-degradable metal materials, such as stainless steel, nickel-titanium alloy or cobalt-chromium alloy. Since these stents are permanently implanted in the blood vessels, a series of problems such as acute occlusion of blood vessels, restenosis, permanent mechanical traction and injury, and chronic inflammatory reactions may occur. In order to solve the limitation of the traditional metal stent, the biodegradable substance is used as an intravascular stent to support the lumen in a certain period of time, and the blood vessel is kept unobstructed, and then gradually degraded or disappeared, which can effectively prevent acute occlusion and restenosis after vasodilation.

There are three main types of biodegradable stents currently being studied: biodegradable polymer scaffolds, biodegradable iron scaffolds, and biodegradable magnesium scaffolds. There are many materials for the preparation of biodegradable polymer scaffolds. Currently, PGLA and PLLA have been approved by the US FDA as bioengineered materials for human body implantation, and have good biocompatibility and biodegradability. However, the main problems of polymer scaffold materials are as follows: (1) insufficient mechanical support strength and weak deformability; (2) poor hydrophilicity, weak cell adsorption, and poor X-ray traceability; (3) organization Poor compatibility, can cause aseptic inflammation; (4) relatively large molecular weight, relatively long degradation cycle, chronic mechanical traction caused a greater loss of the blood vessel wall, easy to stimulate tissue hyperplasia; (5) in itself When released and degraded, it produces more heat, which will cause damage to the blood vessel wall and cause embolism. Therefore, its application range is limited. Pure iron is a corrosive material, and iron is a micronutrient element of the human body. Hemoglobin and many enzymes contain iron. Therefore, iron-based alloy is a potential biodegradable scaffold material. However, the existing research results show that the iron scaffold degrades slowly in the cardiovascular environment of the animal, and in addition, the iron is magnetic and hinders the MRI.

As an intravascular stent material, magnesium alloy has the following outstanding advantages: 1) Degradability. Magnesium alloys have a low corrosion potential, are prone to corrosion in the body environment containing chloride ions, and completely degrade in the body in a slow corrosion manner, thereby avoiding the adverse reactions caused by the retention of metal permanent stents in the blood vessels. 2) High biosafety. As an essential nutrient element of the human body, Mg ranks fourth in the human body only after Ca, K and Na. The World Health Organization recommends that adults need to take about 400 mg of magnesium a day. The physiological function of Mg is mainly reflected in its catalysis or activation of 325 enzymes in the body, which participates in almost all energy metabolism in the body, and plays an important role in neuromotor function, physiological function and prevention of circulatory diseases and ischemic heart disease. Magnesium excretion mainly passes through the urinary system, and absorption of magnesium in the human body does not cause a significant increase in serum magnesium content. Therefore, the use of magnesium alloy as a medical degradable vascular stent material has a good medical safety foundation.

The world's first degradable magnesium alloy stent was processed by Swiss Biotronik using laser engraving technology to process WE43 magnesium alloy tube. Compared with the 316L stainless steel vascular stent, after implantation into the porcine coronary artery for 4 weeks, the angiographic minimum lumen diameter was higher than that of the stainless steel stent group (C Mario, H Griffiths, O Goktekin, et al. Drug-eluting bioabsorbable magnesium Stent, Journal of Interventional Cardiology, 2004, 17: 391-395.). From the feedback of experimental research, the mechanical properties of WE43 magnesium alloy vascular stents need to be further improved. At the same time, the corrosion performance of the WE43 magnesium alloy stent needs to be further improved to provide a longer service life. In particular, the corrosion mode of the WE43 magnesium alloy is similar to that of other commercial magnesium alloys, showing localized corrosion (pitting) rather than the uniform corrosion required clinically. Because only uniform corrosion degradation, the service life of magnesium alloys as implant materials in vivo is predictable. Otherwise, if the magnesium alloy exhibits localized corrosion (pitting), it is prone to local collapse for the vascular stent, and its corroded debris may block the blood vessel, causing serious consequences.

As an intravascular implant material, magnesium alloy must meet the necessary mechanical and morphological requirements during service. On the one hand, the corrosion degradation rate should not be too fast, ensuring the necessary vascular support time, and the degradation mode must be characterized by uniform corrosion degradation. Therefore, the development of magnesium alloys for endovascular scaffolds with in vivo degradation, high toughness, excellent resistance to uniform corrosion degradation, and good biocompatibility has become the focus of research on degradable vascular stent materials.

According to the search of the prior art, Chinese Patent Document No. CN101085377, published on December 12-12, describes a magnesium alloy ultra-thin thin-wall tube forming process for a degradable vascular stent. Its main technical features are: adding yttrium Y, mixed rare earth RE, aluminum Al, calcium Ca, manganese Mn, strontium Sb, zinc Zn, zirconium Zr in pure magnesium, using gas-protective smelting + iron-reducing solvent refining The method comprises the steps of: smelting a magnesium alloy ingot, and then subjecting it to hot extrusion deformation and solution treatment, and cutting a certain length as a workpiece for subsequent processing. One end of the workpiece is cut into a tubular shape, and the other end is processed into a rod shape. Before the drawing, the end of the workpiece is heated, and the pipe ends are drawn. After multiple passes, the diameter can be 2~10 mm. Ultra-thin thin-walled tube with uniform thickness and 0.20mm~1mm. The advantage is that it overcomes the limitation of the forming process such as extrusion, the process cost is low, the formed pipe has uniform wall thickness, uniform structure and good mechanical properties.

However, the technology contains toxic elements such as aluminum Al and strontium Sb, which are recognized as neurotoxic elements, and aluminum-containing magnesium alloys cannot be implanted into the human body. Ingestion of the body can destroy the heart and liver function, and inhalation of high levels of sputum can cause sputum poisoning. The World Health Organization stipulates that the content of strontium and daily intake in water should be less than 0.86 μg/kg per day. The EU stipulates that the content of strontium in food should be less than 20 ppb, while the Sb content in existing patents is as high as 0.1 to 1%. Exceeding the internationally allowed upper limit of entry into the human body. It can be seen that this material of the prior art is in fact not allowed to be implanted as a biological material in the human body.

Summary of the invention

The invention aims at the above-mentioned deficiencies of the prior art, and provides an in vivo degradable magnesium alloy vascular stent material and a manufacturing method thereof, which have better mechanical properties and plastic deformation ability than WE43, ideal uniform corrosion resistance and good performance. Biocompatibility, suitable for use in intravascular and bile duct, pancreatic duct and other internal lumens requiring short-term temporary interventional treatment.

The invention is achieved by the following technical solutions:

The invention relates to a magnesium alloy for in vivo degradable endovascular stent, the composition and the weight percentage thereof being: Nd 1~2.49%, Zn 0.1~2%, Zr 0~0.6%, impurity 0~0.2%, the rest is Mg.

The component weight percentage of the magnesium alloy for the intravascular stent is preferably Nd 2 to 2.49%, Zn 0.1 to 0.3%, and Zr. 0.4~0.6%, the rest is Mg.

The impurities are Fe, Ni, Cu, Al or Si or a combination thereof.

The present invention relates to a method for preparing a magnesium alloy for in vivo endogenous degradable stents, which is obtained by smelting a raw material metal under a protective atmosphere and then casting the ingot, and extruding to obtain a magnesium alloy rod.

The protective atmosphere refers to a protective atmosphere composed of a mixed gas of CO2 and SF6.

The raw material metal is composed of a magnesium block having a purity of 99.99% by weight, a zinc block having a purity of 99.999% by weight, a silver block having a purity of 99.99% by weight, a magnesium-30% cerium alloy, and a magnesium-30% zirconium alloy.

The smelting refers to melting at 700-760 ° C in an electric resistance furnace.

The extrusion means that the extrusion is performed at an extrusion ratio of 5 to 25 in an environment of 250 to 530 °C.

The invention relates to the application of the above-mentioned in vivo degradable medical magnesium alloy, and is used for preparing an endovascular stent and a stent for short-term temporary intervention, such as a cardiovascular stent, a peripheral vascular stent, a bile duct stent, and a bile duct, a pancreatic duct, and the like. Pancreatic duct stent and esophageal stent.

The advantages and benefits of the present invention are:

(1) The magnesium alloy of the present invention can be naturally degraded in the body, and will disappear from the body within a certain period of time after reaching the medical effect, thereby avoiding various adverse reactions caused by the long-term retention of the stent.

(2) The corrosion degradation mode of the magnesium alloy of the present invention is uniform corrosion degradation, which ensures that the service life of the implant material prepared in the alloy is predictable.

(3) The magnesium alloy of the present invention does not contain a poisonous alloying element and has good biocompatibility.

(4) The magnesium alloy of the present invention has excellent mechanical properties, excellent deformability, uniform corrosion resistance and good biocompatibility. The tensile yield strength of the magnesium alloy material prepared by the invention can reach 187~260 MPa, elongation can reach 18~30%, meeting the mechanical properties of the stent material; its corrosion rate in artificial plasma is 0.20~0.40 Mm / year, to meet the corrosion performance requirements of intravascular stent materials; and the material has no obvious cytotoxicity, good blood compatibility, can meet the biocompatibility requirements of intravascular stent materials.

The typical as-cast microstructure of the Mg-Nd-Zn-Zr alloy is composed of an alpha-Mg matrix and a skeletal Mg12Nd second phase distributed along the grain boundary. See Figure 1. After hot extrusion deformation, the alloy structure is remarkably refined, and the typical extrusion deformation microstructure is shown in Fig. 2.

DRAWINGS

Figure 1 shows a typical as-cast microstructure of a Mg-Nd-Zn-Zr magnesium alloy.

Figure 2 shows a typical extruded microstructure of Mg-Nd-Zn-Zr magnesium alloy.

Figure 3 is an SEM image of a cardiovascular stent prepared using a high strength tough Mg-Nd-Zn-Zr magnesium alloy.

detailed description

The embodiments of the present invention are described in detail below. The present embodiment is implemented on the premise of the technical solution of the present invention, and detailed implementation manners and specific operation procedures are given, but the scope of protection of the present invention is not limited to the following implementation. example.

Example 1:

Preparation of Mg-Nd-Zn magnesium alloy ingot by semi-continuous casting method (phi-105×4500 Mm), wherein the alloying elements are 1.0% Nd, 2.0% Zn, and the balance is magnesium. The purity of magnesium in the raw material was 99.99%, and the purity of Zn was 99.999%. The addition of Nd was added in the form of a Mg-30% Nd binary intermediate alloy. Intercept a certain length of ingot, through 540 °C, 10 h solution treatment, extruded into a phi-20 mm round bar, the extrusion temperature is 400 °C, the extrusion ratio is 5-25. The mechanical properties obtained under this process are: tensile strength 258 MPa, yield strength is 187 MPa, elongation is 18%, and hardness is Hv 68. The material has a corrosion rate of 0.40 in artificial plasma. Mm/year. The biological test results show that the material has no obvious cytotoxicity and good biocompatibility.

Example 2:

Preparation of Mg-Nd-Zn-Zr magnesium alloy ingot by semi-continuous casting method (phi-105×4500 Mm), wherein the alloying elements are 2.0% Nd, 0.3% Zn, 0.4% Zr, and the balance is magnesium. The purity of magnesium in the raw material was 99.99%, and the purity of Zn was 99.999%. The addition of Nd and Zr was added in the form of a Mg-30% Nd and Mg-30% Zr binary intermediate alloy, respectively. Intercept a certain length of ingot, through 540 °C, 10 h solution treatment and extrusion into a phi-20 mm round bar, the extrusion temperature is 450 °C, the extrusion ratio is 5-25. The mechanical properties obtained under this process are: tensile strength 238 MPa, yield strength is 188 MPa, elongation is 30%, and hardness is Hv 67. The material has a corrosion rate of 0.30 in artificial plasma. Mm/year, the corrosion mode is uniform corrosion. The biological test results show that the material has no obvious cytotoxicity and good biocompatibility. Can be used as a vascular stent material.

Example 3:

Preparation of Mg-Nd-Zn-Zr magnesium alloy ingot by semi-continuous casting method (phi-105×4500 Mm), wherein the alloying elements are 2.49% Nd, 0.2% Zn, 0.6% Zr, The rest is magnesium. The purity of magnesium in the raw material was 99.99%, and the purity of Zn was 99.999%. The addition of Nd and Zr was added in the form of Mg-30% Nd and Mg-30Zr% binary intermediate alloy. Intercept a certain length of ingot, through 540 °C, 10 h solution treatment, extruded into a phi-20 mm round bar, extrusion temperature of 350 ° C, extrusion ratio of 5-25. The mechanical properties measured by the magnesium alloy prepared under the process are: tensile strength 252 MPa, yield strength is 227 MPa, elongation is 28%, and hardness is Hv 68. The corrosion rate of this material in artificial plasma is 0.20 Mm/year, the corrosion mode is uniform corrosion. The biological test results show that the material has no obvious cytotoxicity and good biocompatibility, and can be used as an intravascular stent material. It can meet the performance requirements of the intravascular stent material. The prototype of the cardiovascular stent prepared from this material is shown in Fig. 3.

Table 1 Chemical composition and mechanical properties of the alloy

实施例 Example	组成 (wt%) Composition (wt%)	挤压温度 ( ℃ ) Extrusion temperature ( °C )	挤压比 Extrusion ratio	抗拉强度（ MPa ）Tensile strength (MPa)	屈服强度（ MPa ） Yield strength ( MPa )	延伸率（％） Elongation rate (%)	硬度（ Hv ）Hardness ( Hv )
1 1	Mg-1Nd-2Zn Mg-1Nd-2Zn	400 400	9 9	258 258	187 187	18 18	68 68
2 2	Mg-2Nd-0.3Zn-0.4Zr Mg-2Nd-0.3Zn-0.4Zr	450 450	9 9	238 238	188 188	30 30	67 67
3 3	Mg-2.49Nd-0.2Zn-0.6Zr Mg-2.49Nd-0.2Zn-0.6Zr	350 350	9 9	252 252	227 227	28 28	68 68

Claims

A magnesium alloy for in vivo degradable endovascular stent, characterized in that its composition and weight percentage are: Nd 1~2.49%, Zn 0.1~2%, Zr 0~0.6%, impurities 0~0.2%, and the rest is Mg.
The magnesium alloy for in vivo degradable endovascular stent according to claim 1, wherein the component weight percentage is Nd 2 to 2.49%, Zn 0.1~0.3%, Zr 0.4~0.6%, and the rest is Mg.
A method for preparing a magnesium alloy for in vivo degradable endovascular stent according to any of the preceding claims, characterized in that the ingot is obtained by smelting the raw material metal under a protective atmosphere, and the magnesium alloy rod is obtained by extrusion. material.
The method according to claim 3, wherein said protective atmosphere means a protective atmosphere composed of a mixed gas of CO2 and SF6.
The method according to claim 3, wherein said raw material metal consists of a magnesium block having a purity of 99.99% by weight, a zinc block having a purity of 99.999% by weight, a silver block having a purity of 99.99% by weight, and a magnesium content of 30% by weight. Niobium alloy and magnesium-30% zirconium alloy.
The method according to claim 3, wherein said smelting means: melting at 700-760 ° C in an electric resistance furnace.
The method according to claim 3, wherein said squeezing means pressing at an extrusion ratio of 5 to 25 in an environment of 250 to 530 °C.
Use of an in vivo degradable medical magnesium alloy according to any of the preceding claims, characterized in that it is used for the preparation of endovascular stents and other stents requiring short-term intervention in the lumen of the body.
The use according to claim 8, wherein said intravascular stent and other stents requiring short-term intervention in the lumen of the body include a cardiovascular stent, a peripheral vascular stent, a bile duct stent, a pancreatic duct stent, and an esophageal stent.