CN100400114C - Biomedical implant material with controllable degradation rate and its application - Google Patents

Abstract

The present invention relates to biomedicine metal implantation material, more specifically a biomedicine implantation material with controllable degrading rate and an application thereof. Magnesium or magnesium alloy is used as a matrix, and the surface of which is coated with a degradable polymer material layer with thickness controlled within 0.01 to 5mm. The biodegradation is completed step by step to ensure the mechanical performance of the material during the degradation process and match the degradation rate with the service time of an implanted device, and therefore, the degradation can be controlled. The biomedicine controllable degrading magnesium and magnesium alloy implantation material which is prepared by the method can be used for making temporary or short-term implantation devices, such as degradable cardiovascular racks, peripheral racks, bone fracture plates and bone nails for internal fixation, tissue engineering racks, etc.

Description

Biomedical implant material with controllable degradation rate and its application

technical field

The invention relates to a biomedical metal implant material, in particular to a biomedical implant material with a controllable degradation rate and its application.

Background technique

At present, most of the degradable materials used in medicine are polymer materials. The degradable polymer materials have the following problems: 1. Low strength, low hardness and rigidity; 2. Poor degradation controllability, degradation time is not proportional to strength and rigidity, degradation In the process, it is easy to lose strength prematurely and cause the device to fail early; 3. The processing stability is poor, and the processing of degradable polymer materials requires special processing environments and equipment; Both patient needs and the development of biomaterials are important.

The corrosion resistance of magnesium and magnesium alloys is poor. The standard potential of pure magnesium is -2.37V, especially in the human physiological environment containing Cl ^- ions. Commonly used pure magnesium and magnesium alloys are corroded and degraded in simulated body fluids. The rate can reach 0.1-5mm/year. The corrosion rate of pure magnesium and magnesium alloys is closely related to the alloying elements, microstructure (grain size, precipitates, etc.), impurity content, processing state and surface state of the material itself. For example, reducing the impurity content and grain size can effectively slow down the corrosion rate of pure magnesium and magnesium alloys. If the surface modification treatment is carried out, the corrosion degradation rate can be controlled at 0.01-5mm/year. Therefore, it is feasible to use the poor corrosion resistance of magnesium alloys to develop new biomedical degradable metal implant materials.

However, commonly used pure magnesium and magnesium alloys have severe pitting corrosion in simulated body fluids. Although local corrosion such as pitting corrosion can be slowed down by alloy optimization, grain size reduction, and impurity content reduction, it is still difficult for implanted devices. In other words, the occurrence of pitting corrosion in the process of corrosion degradation seriously reduces the mechanical properties of the device to a great extent, leading to the premature failure of the device, which may cause serious consequences to patients. Therefore, it is necessary to prevent severe pitting corrosion of degradable pure magnesium and magnesium alloys during the degradation process (especially during the service of implanted devices). In the conventional protection process of pure magnesium and magnesium alloys, surface modification ( Such as anodic oxidation, nitrogen ion surface implantation, laser-assisted treatment, etc.) to protect the surface of magnesium alloys, so as to prevent or slow down the corrosion of magnesium alloys. In the process of developing degradable pure magnesium and magnesium alloys, the method of surface modification can also be used to slow down the corrosion rate of materials, but in the body fluid environment rich in chloride ions, pitting corrosion still inevitably exists in pure magnesium and magnesium alloys phenomenon, there is still a potential threat of premature device failure. Therefore, avoiding local corrosion and adopting more superior degradation control methods are very important for the development of controllable degradation of pure magnesium and magnesium alloys.

my country is rich in magnesium resources, and the advantages and potentials of magnesium alloy metal biomaterials will definitely attract more and more people's attention. The development of biomedical controllable degradable magnesium alloy implant materials and the wide application of pure magnesium and magnesium alloys in the field of implant materials will greatly promote the development of my country's biomaterial industry and magnesium product industry.

Contents of the invention

The purpose of the present invention is to provide a biomedical implant material with a controllable degradation rate and its application, so that during the corrosion degradation process, the degradation rate matches the service time of the implant device, while ensuring the strength of the implant device during service and rigid.

To achieve the above object, the technical solution adopted in the present invention is:

The biomedical implant material with controllable degradation rate is based on pure magnesium or magnesium alloy material, and its surface is coated with a layer of degradable polymer material. The thickness of the coating is controlled at 0.01-5mm; The degradation is carried out step by step, which can ensure the mechanical properties of the material during the degradation process, so as to achieve the purpose of controllable degradation.

The pure magnesium is medical pure magnesium or high-purity magnesium; the magnesium alloy is magnesium-aluminum series alloys, magnesium-manganese series alloys, magnesium-zinc series alloys, magnesium-zirconium series alloys, magnesium rare earth series alloys, magnesium-lithium series alloys, magnesium-calcium series alloys, One of different alloy systems such as magnesium-silver series alloys, or ternary and multi-element magnesium alloys composed of these systems.

The content of alloying elements in the above-mentioned magnesium alloys should basically meet the requirements of biomedical use, so that the degradation amount during the degradation process should be within the dose range that does not cause tissue toxicity; the pure magnesium and magnesium alloys involved mainly include: pure Magnesium (more than 99% by weight), magnesium-aluminum series (in addition to the binary system, mainly including four ternary systems of Mg-Al-Zn, Mg-Al-Mn, Mg-Al-Si, Mg-Al-RE and others Multi-component system, representative alloys such as AZ31, AZ61, AM60, AM50, AE21, AS21, etc., wherein the weight content of aluminum is required to be less than 10%, and the weight content of Zn, Mn, Si and/or RE is less than 5%), magnesium manganese series ( It is mainly composed of binary Mg-0.1～2.5%Mn and a small amount of rare earth, calcium, zinc and other elements. Including Mg-Zn-Zr and Mg-Zn-Cu series, representative alloys such as ZK21, ZK60, ZC62, etc.), magnesium-zirconium series (mainly composed of binary Mg-0.1~1% Zr and adding a small amount of rare earth, zinc and other elements The ternary or multi-element system, representing alloys such as K1A, etc.), magnesium rare earth series (mainly binary Mg-0.1-5% RE and a ternary or multi-element system composed of a small amount of aluminum, zirconium, calcium, zinc and other elements ,), magnesium-lithium series (mainly binary Mg-1~15% Li and a ternary or multi-element system composed of a small amount of aluminum, rare earth, zinc and silicon, representing alloys such as LA91, LAZ933, etc.), magnesium-calcium series (mainly binary Mg-0.1～3%Ca and a ternary system or multiple system composed of a small amount of rare earth, zirconium, zinc and other elements), magnesium-silver series (mainly binary Mg-0.1～12%Ag and adding A ternary system or a multi-element system composed of a small amount of rare earth, zirconium, zinc and other elements, representing one of different alloy systems such as alloys such as QE22, or a ternary and multi-element magnesium alloy composed of these systems. For pure magnesium and magnesium alloys, the corrosion degradation rate in simulated body fluid or body fluid can be controlled within 0.01-5mm/year by changing the composition of the material itself, grain size and heat treatment state.

The degradable polymer materials involved in the present invention can be selected from biodegradable materials commonly used in clinical practice at present, mainly including collagen, gelatin, chitin and other natural degradable polymer materials and polylactide (polylactic acid, PLA), poly Glycolide (polyglycolic acid, PGA), polycyanoacrylate (PACA), polycaprolactone (PCL), polyanhydride (including aliphatic polyanhydride, aromatic polyanhydride, heterocyclic polyanhydride, poly Acid anhydride and cross-linkable polyanhydride, etc.), polyorthoester and/or polyphosphoryl cyanide and other synthetic degradable polymer materials and copolymers between the above polymers, etc. The bone needles, drug-controlled release carriers and stents made of them have been commercialized, and their degradation rates in body fluids and simulated body fluids can be easily controlled from one week to several years. The surface coating process involved in the present invention can be used: dip coating, thermal spraying, sol-gel method, etc., the coating thickness can be controlled between 0.01mm and 5mm according to the needs of the device, and rust removal and oil removal must be carried out before coating , Pretreatment such as phosphating and coupling agents can also be used.

The controllable degradable biomedical metal implant material of the present invention can be used to prepare temporary or short-term medical biological implant devices, such as degradable cardiovascular stents and peripheral stents, bone plates and bone nails for internal fixation, and scaffold materials for tissue engineering.

The biomedical controllable corrosion-degradable pure magnesium and magnesium alloy materials provided by the present invention use a degradable polymer coating to control the early degradation rate of the material, and a magnesium alloy substrate to ensure the mechanical properties during the degradation process.

The present invention has the following advantages:

1. High specific strength and specific rigidity. Compared with degradable polymer materials, biomedical controllable degradable pure magnesium and magnesium alloy materials after surface coating still have higher specific strength and specific rigidity; degradable polymer materials are prone to degradation during the degradation process The mismatch of time and strength leads to premature loss of strength, and the degradation process of the degradable pure magnesium and magnesium alloy after the treatment of the present invention is carried out in two stages: first, the surface degradable polymer coating is gradually degraded, and then the metal magnesium substrate Corrosion degradation of materials, during the material degradation process, the early degradation rate of the material is controlled by the degradable polymer coating, and the mechanical properties during the degradation process are guaranteed by the magnesium alloy matrix, so that the entire implant device can effectively maintain good mechanical properties during the service period. At the same time, pure magnesium and magnesium alloy materials have an elastic modulus close to that of human bone. If bone fixtures and other bone-related devices are made, stress barriers can be effectively avoided, which is very conducive to bone healing.

2. The degradation rate is easy to control. The invention fully combines and exerts the advantages of degradable pure magnesium and magnesium alloys and degradable polymers, and can solve the problems of low strength of degradable polymer materials and rapid strength decline during the degradation process. Ease of control, design the surface degradable polymer coating parameters according to the service period, control the early degradation process, prevent the degradation of early pure magnesium and magnesium alloy materials from corrosion and degradation, avoid local corrosion such as pitting corrosion, and keep the overall material excellent In the later stage of degradation (that is, when the implant is close to the design service period), the magnesium matrix material degrades slowly, even if local corrosion such as pitting occurs, it has little effect on the function of the implant. By optimizing the degradation cycle of the surface coating and the magnesium alloy substrate, biomedical degradable pure magnesium and magnesium alloy materials that meet different clinical needs can be obtained.

3. Safe and practical. Pure magnesium and magnesium alloys are used as implant materials, which have many advantages: 1. Magnesium is rich in resources, relatively low in cost, and widely sourced; 2. The density of magnesium and magnesium alloys is ^about 1.74g/cm Density (1.75g/cm ³ ) is very close; 3. Magnesium and magnesium alloys have high specific strength and specific stiffness; 4. Young's modulus of elasticity of magnesium and magnesium alloys is about 45GP, which is close to the elastic modulus of human bone at about 20GPa , As an implant, it can avoid the stress shielding effect; 5. Magnesium is a constant element in the human body next to calcium, sodium and potassium. The daily requirement of adults is more than 350mg. It participates in a series of metabolic processes in the body. Degradable magnesium and magnesium alloys are finally corroded and degraded in the physiological environment of the body and absorbed or metabolized by the body. The degradation products are mainly magnesium ions needed by the human body. Magnesium is a constant element needed by the human body, and the content of other alloy elements contained in Within the scope of biomedical use, the selected degradable polymer materials are also commonly used clinically at present, so it is safe and has great advantages to prepare controllable degradable medical implant devices using the treated pure magnesium and magnesium alloys of the present invention and application prospects.

Detailed ways

Example 1

Use pure magnesium to make a coronary stent sample (after polishing, the wire diameter is 70-80 μm), ultrasonically clean it in acetone and alcohol for 5 minutes, dry it in a vacuum oven, and then put it into a polylactic acid (PLA) solution ( Soak in 0.1g/mL) for 10 minutes, use a stepping motor to pull the pure magnesium sample out of the solution at a uniform speed, centrifuge at 1000 rpm for 1 minute, and then put the bracket in a vacuum drying oven to dry, according to the thickness requirements The number of times of dipping is repeated, the thickness of the coating in this embodiment is 11 μm, after treatment, it will be completely corroded and degraded after being soaked in the simulated plasma solution prepared in Table 1 for about 9 months.

Since the corrosion rate of pure magnesium materials can be adjusted by factors such as impurity content, grain size and heat treatment, the degradation rate of polylactic acid can also be controlled according to the molecular weight of polylactic acid and the thickness of the coating, so according to the above process The medical The degradation rate of controllable degradable pure magnesium coronary stent can be optimized from two aspects: pure magnesium and polylactic acid.

Table 1: Artificial plasma composition

compound NaCl CaCl₂ KCl MgSO4 NaHCO₃ Na₂HPO₄ NaH₂PO₄ Concentration, mg/L 6800 200 400 100 2200 126 26

Example 2

After the AZ31B magnesium alloy was polished, it was ultrasonically cleaned in acetone and alcohol for 5 minutes, dried in a vacuum oven, and then immersed in polyglycolic acid (PGA) solutions (0.2g/mL) of different molecular weights for 20 minutes. Pull the AZ31B magnesium alloy sample out of the solution at a uniform speed with a stepping motor, centrifuge it at 1000 rpm for 1 minute, then put the bracket into a vacuum drying oven to dry, and repeat the number of times of dipping according to the thickness requirements. In this example The coating thickness was 23 μm.

Since the corrosion rate of the AZ31B magnesium alloy material can be adjusted by factors such as impurity content, grain size and heat treatment, the degradation rate of polyglycolic acid can also be controlled according to the molecular weight and the thickness of the coating, so the medical can be prepared according to the above process. Controlled Degradation The degradation rate of magnesium alloy materials can be optimized from two aspects: the alloy matrix and the surface polyglycolic acid coating.

Example 3

After high-purity magnesium (99.98%) is polished, it is ultrasonically cleaned in acetone and alcohol for 5 minutes, dried in a vacuum oven, and then put into a copolymer of polylactic acid and polyglycolic acid (PLGA) solution (0.05g/mL) Soak in medium for 40 minutes, use a stepping motor to pull the pure magnesium sample out of the solution at a uniform speed, centrifuge at 1000 rpm for 30 seconds, then put the bracket in a vacuum drying oven to dry, and repeat the dipping times according to the thickness requirements , the thickness of the coating in this embodiment is 8 μm. .

Since the corrosion rate of pure magnesium materials can be adjusted by factors such as impurity content, grain size and heat treatment, the degradation rate of the copolymer of polylactic acid and polyglycolic acid can also be controlled according to the ratio of the two and the thickness of the coating, so The degradation rate of the medical controllable degradable magnesium alloy material prepared by the above process can be optimized from two aspects of the alloy matrix and the coating of polylactic acid and polyglycolic acid on the surface.

Example 4

After polishing the AM60 magnesium alloy, ultrasonically clean it in acetone and alcohol for 5 minutes respectively, dry it in a vacuum drying oven, then put it into the molten polylactic acid liquid and soak it for 10 minutes, take out the material and put it into a suitable mold to cool , After demoulding, it is trimmed and used. The thickness of the coating in this embodiment is 1mm.

Since the corrosion rate of AM60 magnesium alloy material can be adjusted by factors such as impurity content, grain size and heat treatment, the degradation rate of polylactic acid can also be controlled according to the molecular weight and the thickness of the coating, so the medical controllable The degradation rate of magnesium alloy materials can be optimized from two aspects: alloy matrix and surface polylactic acid coating.

Example 5

After the ZK60 magnesium alloy is polished, it is ultrasonically cleaned in acetone and alcohol for 5 minutes, dried in a vacuum oven, and then soaked in polycaprolactone (PCL) solutions (0.1g/mL) of different molecular weights for 30 minutes , use a stepping motor to pull the ZK60 magnesium alloy sample out of the solution at a uniform speed, centrifuge it at 1000 rpm for 1 minute, then put the bracket into a vacuum drying oven to dry, and repeat the number of times of dipping according to the thickness requirements. In this embodiment The coating thickness is 18 μm.

Since the corrosion rate of ZK60 magnesium alloy material can be adjusted by factors such as impurity content, grain size and heat treatment, the degradation rate of polycaprolactone can also be controlled according to the molecular weight and the thickness of the coating, so according to the above process prepared medical The degradation rate of controllable degradation magnesium alloy materials can be optimized from two aspects of alloy substrate and surface polycaprolactone coating.

Example 6

The difference with embodiment 5 is:

The magnesium alloy is MB1, the degradable polymer material is collagen (0.5g/mL), the soaking time is 10 minutes, and the coating thickness is 4mm.

Example 7

The difference with embodiment 5 is:

The magnesium alloy is K1A, the degradable polymer material is equal volumes of gelatin and chitin (0.1g/mL), the soaking time is 15 minutes, and the coating thickness is 0.9mm.

Example 8

The difference with embodiment 5 is:

The magnesium alloy is LA91, the degradable polymer material is polyorthoester (0.05g/mL), the soaking time is 40 minutes, and the coating thickness is 0.4mm.

Example 9

The difference with embodiment 5 is:

The magnesium alloy is QE22, the degradable polymer material is polycyanoacrylate (0.2g/mL), the soaking time is 25 minutes, and the coating thickness is 2mm.

Claims (6)

1. the biological and medicinal implant material of controllable degradation rate, it is characterized in that: with pure magnesium or magnesium alloy materials is matrix, its surface-coated one deck degradable high polymer material, the THICKNESS CONTROL of coating is at 0.01-5mm;

Described degradable high polymer material is: natural degradable macromolecular material, or the copolymer between the polybutylcyanoacrylate, poly-anhydride, poe and/or these synthesized degradable macromolecular materials of polyphosphazene or above-mentioned polymer.

2. according to the biological and medicinal implant material of the described controllable degradation rate of claim 1, it is characterized in that: described pure magnesium is medical pure magnesium or high-purity magnesium; Magnesium alloy is, magnalium, magnesium-manganese alloy, magnesium-zinc alloy, magnesium zircaloy, magnesium-rare earth alloy, magnesium lithium alloy, magnesium calcium alloy, magnesium silver alloy a kind of or the ternary system or the polynary system magnesium alloy that are formed by these system combinations.

3. according to the biological and medicinal implant material of the described controllable degradation rate of claim 1, it is characterized in that: described pure magnesium refers to the magnesium of magnesium weight content 〉=99%; The weight content of aluminum＜10% in the magnesium alloy, the weight content of Zn, Mn, Si or RE≤5%, the weight content of Zr≤1%, the weight content of Li≤15%, the weight content of Ca≤3%, the weight content of Ag≤12%.

4. according to the biological and medicinal implant material of the described controllable degradation rate of claim 1, it is characterized in that:

Described natural degradable macromolecular material is collagen protein, gelatin and/or chitin; Poly-anhydride is aliphatic poly anhydride, fragrant adoption anhydride or heterocycle adoption anhydride.

5. the application of the biological and medicinal implant material of the described controllable degradation rate of claim 1 is characterized in that: pure magnesium or magnesium alloy materials are used for the temporary transient or short-term bio-medical implant devices of preparation.

6. according to the application of the biological and medicinal implant material of the described controllable degradation rate of claim 5, it is characterized in that: described implant devices is degradable angiocarpy bracket, cardiovascular peripheral bracket, internal fixation with blade plate or internal fixation nail.