阅读说明：本技术 降低医用镁基材料腐蚀速率的可降解聚碳酸酯涂层的制备方法 (Preparation method of degradable polycarbonate coating for reducing corrosion rate of medical magnesium-based material ) 是由 李小杰 潘凯 魏玮 刘仁 刘晓亚 于 2020-05-08 设计创作，主要内容包括：本发明公开了一种降低医用镁基材料腐蚀速率的可降解聚碳酸酯涂层的制备方法,首先通过开环共聚反应,合成侧基带有“烯基”的聚碳酸酯共聚物。将其作为涂层的基体树脂并添加多臂硫醇交联剂及其他助剂,通过快速的“硫醇-烯”加成反应实现涂层的交联固化,在医用镁金属表面制备得到了一种可降解聚碳酸酯涂层。涂层具有独特的表面溶蚀降解行为,从根本上避免了传统商品化聚酯由于其本体降解模式及酸性降解产物造成的防护性能下降甚至加速镁基材的腐蚀的问题,具有优异的长效防腐性能,可以有效延缓镁基材的降解速率。此外,所制备得的聚碳酸酯涂层具有优异的表面硬度、良好的机械性能、牢固的附着力以及良好的生物相容性。(The invention discloses a preparation method of a degradable polycarbonate coating for reducing the corrosion rate of a medical magnesium-based material. The modified polycarbonate resin is used as matrix resin of a coating, a multi-arm thiol cross-linking agent and other additives are added, the cross-linking and curing of the coating are realized through rapid thiol-ene addition reaction, and the degradable polycarbonate coating is prepared on the surface of medical magnesium metal. The coating has unique surface corrosion degradation behavior, fundamentally avoids the problems of the traditional commercialized polyester that the protective performance is reduced and the corrosion of the magnesium base material is even accelerated due to the body degradation mode and the acidic degradation product, has excellent long-acting corrosion resistance, and can effectively delay the degradation rate of the magnesium base material. In addition, the prepared polycarbonate coating has excellent surface hardness, good mechanical property, firm adhesion and good biocompatibility.)

1. A preparation method of a degradable polycarbonate coating for reducing the corrosion rate of a medical magnesium-based material is characterized by comprising the following steps:

s1, preparing a polycarbonate copolymer with a molecular weight of 1000-100000 Da through ring-opening copolymerization of at least two six-membered cyclic carbonate monomers, wherein the polycarbonate copolymer is degradable polycarbonate with alkenyl on a side group;

s2, dissolving a thiol crosslinking agent and the polycarbonate copolymer prepared in the step (S1) in an organic solvent to prepare a mixed solution with the solid content of 1-20 wt%, and performing thiol-ene addition reaction for crosslinking and curing;

s3, coating the mixed solution obtained in the step (S2) on the surface of a clean medical magnesium alloy base material; and carrying out rapid curing treatment after the coating is dried to obtain the degradable polycarbonate coating.

2. The method for preparing the degradable polycarbonate coating for reducing the corrosion rate of the medical magnesium-based material according to claim 1, wherein the six-membered cyclic carbonate monomer in the step of S1 comprises: 1, 3-dioxan-2-one TMC, 5-methyl-5-allyloxycarbonyl-1, 3-dioxan-2-one MAC, 5-allyloxy-1, 3-dioxan-2-one ATMC, 2- (methacrylamido) trimethylene carbonate MATC, 5-methyl-5-acryloyloxy-1, 3-dioxan-2-one AC and 5-methyl-5-methacryloyloxy-1, 3-dioxan-2-one MA.

3. The method for preparing the degradable polycarbonate coating for reducing the corrosion rate of the medical magnesium-based material according to claim 1, wherein the ring-opening copolymerization in the step S1 is carried out under anhydrous and oxygen-free conditions, and the reaction temperature is 20-160 ℃; the structure of the prepared polycarbonate copolymer is shown as the following formula:

wherein:

R₁independently selected from H, CH₃One of (1);

R₂independently selected from H, -OC (O) -CH₂＝CH₂、-NH-C(O)-CH(CH₃)＝CH₂、-O-CH₂-CH＝CH₂、-COO-CH＝CH₂and-OC (O) -C (CH)₃)＝CH₂One of (1);

R₃independently selected from H, CH₃One of (1);

R₄independently selected from H, -OC (O) -CH₂＝CH₂、-NH-C(O)-CH(CH₃)＝CH₂、-O-CH₂-CH＝CH₂、-COO-CH＝CH₂and-OC (O) -C (CH)₃)＝CH₂One of (1);

R₂、R₄not H at the same time;

x and y are positive integers, and x + y is less than 400.

4. The method for preparing the degradable polycarbonate coating layer for reducing the corrosion rate of the medical magnesium-based material according to claim 1, wherein the ring-opening copolymerization process of step S1 comprises adding an initiator and a catalyst, wherein the initiator is a small molecule or a high molecule containing a hydroxyl functional group, and comprises benzyl alcohol and isopropanol; the catalyst is one or more of stannous octoate, diazabicyclo, 1,5, 7-triazabicyclo [4.4.0] dec-5-ene and 1-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene.

5. The method of claim 1, wherein the thiol crosslinking agent in step S2 comprises one or more of trimethylolpropane tris (3-mercaptopropionate), trimethylolpropane tris (2-mercaptoacetate), pentaerythritol tetrakis (3-mercaptopropionate), and dithiothreitol, and the molar ratio of thiol in the thiol crosslinking agent to unsaturated bonds in the polycarbonate copolymer is 9: 10 to 3: 2.

6. The method of claim 1, wherein the organic solvent in step S2 is one of dichloromethane, dimethyl sulfoxide, tetrahydrofuran and ethyl acetate.

7. The method for preparing the degradable polycarbonate coating layer for reducing the corrosion rate of the medical magnesium-based material as claimed in claim 1, wherein an auxiliary agent is added during the step of S2, the auxiliary agent is one or two of an initiator and a bioactive substance, the initiator is one or more of Irgacure 2959, ethyl pyruvate and phenyl-2, 4, 6-trimethylbenzoyllithium phosphonate, and the bioactive substance is one or two of RGD peptide and 2-methacryloyloxyethyl phosphorylcholine MPC; in the mixed solution, the content of the initiator is 0-0.1 wt%, and the content of the bioactive substance is 0-10 wt%.

8. The method of claim 1, wherein the rapid curing conditions of step S3 include radiation, heat, or a combination thereof; radiation includes electron beam, UV light, visible light, infrared light, and other forms of electromagnetic radiation.

9. Use of the degradable polycarbonate coating of claim 1 for reducing the corrosion rate of medical magnesium-based materials for corrosion control and/or improving the bioactivity of device surfaces on medical devices made of magnesium and its alloys.

Technical Field

The invention relates to a functional material, in particular to the technical field of surface anticorrosion treatment of medical magnesium-based materials, and specifically relates to a preparation method of a degradable polycarbonate coating for reducing the corrosion rate of the medical magnesium-based materials.

Background

In recent years, magnesium alloys have a wide application prospect in the field of medical implants due to good biocompatibility and biodegradability, and are receiving wide attention of researchers. However, magnesium alloys are very susceptible to degradation due to their reactive chemical properties, which can cause local cytotoxicity, hydrogen bubble enrichment, and premature failure of mechanical properties of the material. These problems limit the clinical application of magnesium-based implants. In order to solve the problems, a polymer coating, especially a degradable polymer coating, is prepared on the surface of the magnesium alloy, and is an effective method for controlling the corrosion rate of the magnesium alloy in both research and clinical application.

Most of the carriers of the currently common drug eluting stents are commercialized degradable polyesters such as polylactic acid CN109161882A and copolymers thereof. The degradation mode is a body dissolution type, the degradation mode is first-order kinetics, the degradation speed is uncontrollable, the polymer continuously decreases from inside to outside of the molecular weight in the corrosion process, the mechanical property and the integrity of the coating are rapidly damaged, the coating is easily corroded to penetrate through the exposed matrix, the protection effect is lost in the service period of the device, and the corrosion rate of the magnesium substrate is too high. In addition, the degradation products of the polyester are acidic, can react with alkaline magnesium alloy base materials and corrosion products thereof to further accelerate corrosion of magnesium alloy devices, and can easily cause over-high local acidity in vivo, generate toxic and side effects such as inflammatory reaction, thrombus and the like, thereby threatening human health.

CN102327862A discloses a method for preparing surface erosion type polymer coating such as polycarbonate, polyanhydride, polyorthoester, etc. on magnesium alloy device, the degradation behavior is surface erosion type degradation, i.e. the degradation is gradually degraded from the surface to the inner part of the material, the whole degradation process is linear process, the degradation rate is controllable linearly, and is zero order kinetic degradation, there is also literature report that, compared with bulk erosion type polyester commercial degradable polymer represented by PC L, surface erosion aliphatic carbonate PTMC provides good protection effect on the surface of magnesium alloy before the degradation is complete because of the surface erosion degradation behavior, and the degradation products of the polymer are near neutral carbon dioxide and water, thus fundamentally avoiding magnesium base accelerated corrosion caused by degradation, and no inflammatory reaction caused by the stimulation of the degradation products (Juan Wang, et al, Acta materials, 9(2013) 8678-8689).

However, in many of the above conventional methods, a surface-eroding polymer having a simple structure and a single function is applied to the surface of a magnesium alloy material or an instrument. The polymer structure lacks structural design and the basic properties of these polymer coatings, such as hardness and mechanical properties, are not fully satisfactory due to their own physicochemical properties, such as glass transition temperature, limitations of mechanical properties. Aliphatic carbonate PTMC due to its lower glass transition temperature (T)_gAbout 17 ℃), the prepared coating has poor dimensional stability and mechanical properties in the environment of high temperature of human body, and the surface hardness of the coating is also low. The polyanhydride is brittle, and meanwhile, the degradation intermediate product is organic acid, and the problem of acidic degradation products existing in the polyester polymer also exists. Meanwhile, the main chains of the polymers lack functional groups, and in order to improve the bioactivity of the coating surface, the surface of the polymer is often required to be further coated or modified (CN 205379387U; CN 102327862A). The above problem limitsThe practical application of the surface erosion type polymer.

Therefore, a surface-etching-type degradable coating material with good mechanical properties, excellent surface hardness, scratch resistance and convenient functionalization is needed. Crosslinking of the coating is an effective means to solve the above problems, but crosslinking may affect the degradation behavior of the coating or even render the coating undegradable, and therefore the design of the polymer structure as well as the coating formulation and preparation method is required.

The invention provides a preparation method of a rapid-curing degradable polycarbonate coating for reducing the corrosion rate of a medical magnesium-based material, which not only has the surface-corrosion-type degradation behavior and the formation of a neutral degradation product and a curing network, but also effectively delays the degradation rate of the coating and further prolongs the protective performance of the coating. And the biological coating has pencil hardness and adhesion comparable to industrial coatings, as well as excellent mechanical properties. In addition, the coating preparation method can be used for simply and rapidly introducing the functional molecules with biological activity into the coating cross-linked network through chemical bonding in the coating curing process. Can be applied to magnesium-based medical instruments such as magnesium-based vascular stents, magnesium-based bone fixation instruments (bone screws and bone splints), anastomats and the like. For the sake of clarity, the magnesium-based material and its medical implant device are hereinafter referred to as medical magnesium-based materials.

Disclosure of Invention

In view of the deficiencies of the prior art solutions set forth above, the present invention aims to provide a method for preparing a degradable polycarbonate coating having surface erosion degradation behavior that reduces the corrosion rate of medical magnesium-based materials. Compared with polycarbonate without crosslinking, the coating prepared by the invention has the advantages of obviously reduced degradation rate, obviously improved corrosion resistance, excellent scratch resistance, firm adhesion, good mechanical property and excellent biocompatibility. In the preparation process of the coating, functional molecules represented by functional drugs can be chemically bonded in a coating curing network through convenient chemical modification, so that the coating has different medical functions.

The object of the present invention is achieved by the following means.

A preparation method of a fast-curing degradable polycarbonate coating for reducing the corrosion rate of a medical magnesium-based material comprises the following steps of preparing a polymer functional coating for reducing the corrosion rate on the surface of the magnesium-based material:

s1, taking a functionalized six-membered cyclic carbonate monomer as a feeding monomer, and preparing a degradable polycarbonate copolymer with the molecular weight of 1000-100000 Da through polymerization of two or more monomers;

s2, dissolving a cross-linking agent with low biological toxicity (preferably a thiol cross-linking agent) and the polycarbonate copolymer prepared from S1 in an organic solvent, wherein the solid content is 1-20 wt%;

s3, coating the mixed solution prepared in the step S2 on the surface of a clean medical magnesium alloy base material; and carrying out rapid curing treatment after the coating is dried, and finally obtaining the functional coating.

Specifically, the functionalized six-membered cyclic carbonate monomer in the first step is: 1, 3-dioxan-2-one (TMC), 5-methyl-5-allyloxycarbonyl-1, 3-dioxan-2-one (MAC), 5-allyloxy-1, 3-dioxan-2-one (ATMC), 2- (methacrylamido) trimethylene carbonate (MATC), 5-methyl-5-acryloyloxy-1, 3-dioxan-2-one (AC) and 5-methyl-5-methacryloyloxy-1, 3-dioxan-2-one (MA). The specific structure is as follows:

specifically, the polycarbonate copolymer prepared in the first step has a double bond in a pendant group, as shown in the following structural formula.

Wherein:

R₁independently selected from H, CH₃；

R₂Independently selected from H, -OC (O) -CH₂＝CH₂、-NH-C(O)-CH(CH₃)＝CH₂、-O-CH₂-CH＝CH₂、 -COO-CH＝CH₂and-OC (O) -C (CH)₃)＝CH₂；

R₃Independently selected from H, CH₃；

R₄Independently selected from H, -OC (O) -CH₂＝CH₂、-NH-C(O)-CH(CH₃)＝CH₂、-O-CH₂-CH＝CH₂、 -COO-CH＝CH₂and-OC (O) -C (CH)₃)＝CH₂；

R₂、R₄Cannot be simultaneously H;

x and y are positive integers, and x + y is less than 400.

Specifically, the polymerization reaction in S1 is ring-opening copolymerization carried out under oxygen-free water conditions, and the initiator is a small molecule or a polymer containing a hydroxyl functional group, such as a small molecule monohydric alcohol containing a hydroxyl group represented by benzyl alcohol and isopropanol; the catalyst is one or more of stannous octoate, DBU (diazabicyclo), TBD (1,5, 7-triazabicyclo [4.4.0] dec-5-ene) and MTBD (1-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene). The reaction temperature is 20-160 ℃.

Specifically, the thiol crosslinking agent of S2 is trimethylolpropane tris (3-mercaptopropionate) (TMPMP), trimethylolpropane tris (2-mercaptoacetate) (TTMA), pentaerythritol tetrakis (3-mercaptopropionate) (PETMP), and Dithiothreitol (DTT);

more specifically, the molar ratio of the thiol in the thiol crosslinking agent to the unsaturated bond in the polycarbonate copolymer is 9: 10 to 3: 2.

More specifically, the mixed solution is also added with an auxiliary agent, wherein the auxiliary agent is one or two of an initiator and a bioactive substance, the initiator is one or more of Irgacure 2959, ethyl pyruvate and phenyl-2, 4, 6-trimethyl benzoyl lithium phosphonate (L AP), the bioactive substance is one or two of RGD peptide and 2-Methacryloyloxyethyl Phosphorylcholine (MPC), and preferably, the content of the initiator is 0-0.1 wt% and the content of the bioactive substance is 0-5 wt%.

Specifically, the organic solvent in the second step is dichloromethane, dimethyl sulfoxide, tetrahydrofuran or ethyl acetate.

Specifically, the rapid curing conditions described in the third step include radiation, heat, or a combination thereof. Radiation includes UV light, electron beams, and other forms of light such as visible light, infrared light, and other forms of electromagnetic radiation.

The invention prepares a degradable coating which is crosslinked and solidified through a thiol-ene chemical reaction. Firstly, a polycarbonate copolymer with alkenyl (or alkene) functional groups is prepared, then, a multifunctional thiol is added as a cross-linking agent, and a biomedical coating with excellent corrosion resistance, good mechanical property and adhesive force and excellent scratch resistance can be prepared through a rapid free radical reaction.

The beneficial technical effects of the invention are as follows:

the degradable polycarbonate coating prepared by the method can effectively reduce the corrosion rate of the medical magnesium-based material and improve the biocompatibility of the surface of the medical magnesium-based material. Due to the unique surface corrosion behavior, the magnesium base material is well protected until the magnesium base material is completely degraded, and corrosion caused by contact between a corrosion medium and the base material is prevented; fundamentally avoids the problems of the conventional commercialized polyester that the protective performance is reduced and the corrosion of the magnesium substrate is accelerated due to the body degradation mode and the acidic degradation product, and has excellent long-acting corrosion resistance. In addition, the coating of the present invention solves the problems of poor mechanical properties, surface hardness and abrasion resistance of surface erosion-degradable polymers represented by polytrimethylene carbonate through "thiol-ene" chemical crosslinking, while still achieving complete degradation of the coating. It is also convenient to impart different biological functions to the coating by chemically modifying functional molecules represented by functional drugs in the crosslinked network of the coating.

Drawings

FIG. 1 shows the NMR spectrum of polycarbonate copolymer 1 in example 1.

FIG. 2 is a total reflection IR spectrum of the polymer coating material of example 1 before and after photocuring.

FIG. 3 is a scanning electron microscope photograph of the surface of the bare magnesium alloy in test example 1, and six samples in examples 1 to 3 and comparative examples 1 to 2, after immersion in human body simulated fluid (SBF) at 37 ℃ for 0, 5, 15, and 30 days.

FIG. 4 is a graph showing the cell viability of different surfaces of the bare magnesium alloy, example 1, example 3, example 5, comparative example 1 and comparative example 2 in test example 3, after culturing the same on the surface for 24h and 48h using L929 cells.

Detailed Description

The invention is further illustrated below with reference to specific embodiments. It is to be understood that the present invention is not limited to the following embodiments, which are regarded as conventional methods unless otherwise specified. The materials are commercially available from the open literature unless otherwise specified.