CN111420129A - Preparation method of degradable polycarbonate coating for reducing corrosion rate of medical magnesium-based materials - Google Patents
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Abstract
Translated fromChinese
Description
Translated fromChinese技术领域technical field
本发明涉及功能材料，尤其是医用镁基材料表面防腐蚀处理技术领域，具体是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。The invention relates to functional materials, in particular to the technical field of anti-corrosion treatment on the surface of medical magnesium-based materials, in particular to a preparation method of a degradable polycarbonate coating that reduces the corrosion rate of medical magnesium-based materials.
背景技术Background technique
近年来，镁合金由于其良好的生物相容性和生物可降解性在医用植入物领域具有广阔的应用前景，受到研究人员的广泛关注。然而，镁合金由于其活泼的化学性质极易发生降解，容易造成局部的细胞毒性、氢气气泡的富集，以及材料力学性能过早的破坏。这些问题限制了镁基植入物的临床应用。针对这些问题，在镁合金表面制备一层聚合物涂层，尤其是可降解聚合物涂层无论在研究还是临床应用中都是一种控制镁合金腐蚀速率行之有效的方法。In recent years, magnesium alloys have attracted extensive attention of researchers due to their promising biocompatibility and biodegradability in the field of medical implants. However, magnesium alloys are easily degraded due to their active chemical properties, which are prone to local cytotoxicity, enrichment of hydrogen gas bubbles, and premature destruction of material mechanical properties. These problems limit the clinical application of magnesium-based implants. In view of these problems, the preparation of a polymer coating on the surface of magnesium alloys, especially the degradable polymer coating, is an effective method to control the corrosion rate of magnesium alloys in both research and clinical applications.
目前常用的药物洗脱支架的载体多为商品化可降解聚酯如聚乳酸CN109161882A及其共聚物。其降解模式为本体溶蚀型，其降解方式为一级动力学，降解速度不可控制，在腐蚀过程中聚合物的从分子量内而外一起持续下降，涂层的机械性能和完整性受到急剧破坏，很容易被腐蚀穿透暴露基体，往往在器件服役期间就失去保护功效，导致镁基材腐蚀速率过快。此外，这些聚酯的降解产物为酸性，能够与碱性的镁合金基材及其腐蚀产物反应进一步加速镁合金器件的腐蚀，同时也容易导致体内局部酸性过高，产生炎症反应和血栓等毒副作用，威胁人类的健康。Currently, the commonly used carriers of drug-eluting stents are mostly commercial degradable polyesters such as polylactic acid CN109161882A and its copolymers. Its degradation mode is bulk erosion type, its degradation mode is first-order kinetics, and the degradation rate is uncontrollable. During the corrosion process, the molecular weight of the polymer continues to decrease from the inside to the outside, and the mechanical properties and integrity of the coating are sharply damaged. It is easy to be corroded to penetrate the exposed substrate, and often loses its protective effect during the service of the device, resulting in an excessively fast corrosion rate of the magnesium substrate. In addition, the degradation products of these polyesters are acidic, which can react with alkaline magnesium alloy substrates and their corrosion products to further accelerate the corrosion of magnesium alloy devices. At the same time, it is easy to cause excessive local acidity in the body, resulting in inflammatory reactions and thrombosis. side effects that threaten human health.
CN102327862A公开了一种在镁合金器件上制备表面溶蚀型聚合物涂层如聚碳酸酯、聚酸酐、聚原酸酯等，其降解行为表面溶蚀型降解，即由材料表面向内部逐渐降解，整个降解过程为线性过程，降解速率线性可控，且为零级动力学降解。也有文献报道证明，与以PCL 为代表的本体溶蚀型聚酯型商品化可降解聚合物相比，表面侵蚀脂肪族碳酸酯PTMC在镁合金表面由于其表面溶蚀降解行为在其降解完全之前，一直提供很好的保护效果；并且聚合物的降解产物为近中性二氧化碳和水，从根本上避免了因降解造成的镁基加速腐蚀，并且在不会由于降解产物的刺激造成炎症反应(Juan Wang,et.al,Acta Biomaterialia,9(2013) 8678–8689)。CN102327862A discloses a kind of surface erosion type polymer coating such as polycarbonate, polyanhydride, polyorthoester, etc. prepared on magnesium alloy devices. The degradation process is a linear process, the degradation rate is linearly controllable, and the degradation is zero-order kinetics. It has also been reported in the literature that, compared with the bulk-erosion-type polyester-type commercial degradable polymers represented by PCL, the surface-eroding aliphatic carbonate PTMC on the surface of magnesium alloys has been maintained until its degradation is complete due to its surface-erosion degradation behavior. Provides a good protective effect; and the degradation products of the polymer are near-neutral carbon dioxide and water, which fundamentally avoids the accelerated corrosion of magnesium groups caused by degradation, and does not cause inflammatory reactions due to the stimulation of degradation products (Juan Wang , et.al, Acta Biomaterialia, 9 (2013) 8678–8689).
然而，上述现有的方法多是将结构简单功能单一的表面侵蚀型聚合物施加在镁合金材料及器械表面。聚合物结构缺乏结构设计并且由于其本身物理化学的性质如玻璃化转变温度，机械性能的限制，这些聚合物涂层的基本性能如硬度，力学性能不尽人意。脂肪族碳酸酯 PTMC由于其较低的玻璃化转变温度(Tg约17℃)，制备得到的涂层在人体较高温度的环境中具有差的尺寸稳定性和力学性能，涂层的表面硬度也很低。聚酸酐较脆，同时降解中间产物为有机酸，同样存在聚酯聚合物存在的酸性降解产物的问题。同时，这些聚合物主链缺乏功能基团，为了提高涂层表面的生物活性，往往需要在其表面进行进一步涂装或改性处理 (CN205379387U；CN102327862A)。上述问题限制了表面侵蚀型聚合物的实际应用。However, most of the above-mentioned existing methods apply a surface-eroding polymer with a simple structure and a single function to the surface of magnesium alloy materials and instruments. The polymer structure lacks structural design and the basic properties such as hardness and mechanical properties of these polymer coatings are unsatisfactory due to their inherent physical and chemical properties such as glass transition temperature and mechanical properties. Aliphatic carbonate PTMC due to its lower glass transition temperature (Tg about 17 ℃), the prepared coating has poor dimensional stability and mechanical properties in the environment of higher temperature of the human body, the surface hardness of the coating Also low. Polyanhydrides are relatively brittle, and at the same time, the intermediate products of degradation are organic acids, and there is also the problem of acidic degradation products existing in polyester polymers. At the same time, these polymer main chains lack functional groups. In order to improve the biological activity of the coating surface, further coating or modification treatment is often required on the surface (CN205379387U; CN102327862A). The above problems limit the practical application of surface-erosive polymers.
因此，需要一种具有良好的力学性能，优异的表面硬度，耐刮擦性能和方便功能化的表面溶蚀型可降解涂层材料。实现涂层的交联是解决上述问题的有效手段，但是交联可能影响涂层的降解行为甚至致使涂层无法降解，因此需要对聚合物结构以及涂层配方和制备方法进行设计。Therefore, there is a need for a surface erosion-type degradable coating material with good mechanical properties, excellent surface hardness, scratch resistance and convenient functionalization. Cross-linking of coatings is an effective means to solve the above problems, but cross-linking may affect the degradation behavior of coatings or even make coatings unable to degrade. Therefore, it is necessary to design polymer structures, coating formulations and preparation methods.
本发明提出一种降低医用镁基材料腐蚀速率的快速固化可降解聚碳酸酯涂层的制备方法, 不仅具有表面溶蚀型的降解行为以及中性降解产物，固化网络的形成，有效延缓了涂层降解的速率，进一步延长了涂层的保护性能。并且该生物涂层具有堪与工业涂层相比的铅笔硬度和附着力，以及优异的机械性能。此外，该涂层制备方法在涂层的固化过程中简易快速的将具有生物活性的功能分子通过化学键合引入到涂层交联网络中。可以应用于镁基血管支架、镁基骨固定器械(骨螺钉、骨夹板)、吻合器等镁基医疗器械。为便于清楚叙述，镁基材料及其医用植入器件以下均称为医用镁基材料。The present invention proposes a preparation method of a rapidly curing degradable polycarbonate coating that reduces the corrosion rate of medical magnesium-based materials, which not only has surface erosion-type degradation behavior and neutral degradation products, but also forms a curing network, effectively delaying the coating process. The rate of degradation further extends the protective properties of the coating. And the biocoating has pencil hardness and adhesion comparable to industrial coatings, as well as excellent mechanical properties. In addition, the coating preparation method can easily and quickly introduce biologically active functional molecules into the cross-linked network of the coating through chemical bonding during the curing process of the coating. It can be applied to magnesium-based medical devices such as magnesium-based blood vessel stents, magnesium-based bone fixation devices (bone screws, bone splints), and staplers. For the convenience of clear description, the magnesium-based materials and their medical implant devices are hereinafter referred to as medical magnesium-based materials.
发明内容SUMMARY OF THE INVENTION
鉴于以上陈述的已有方案的不足，本发明旨在提供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，该涂层具有表面溶蚀降解行为。并且相较于没有交联的聚碳酸酯，本发明所制备涂层的降解速率明显降低和防腐性能显著提高，同时还具有优异的耐刮擦性、牢固的附着力、良好的机械性能以及出色的生物相容性。在本发明涂层的制备过程中，还可以通过便捷的化学改性，在涂层固化网络中化学键合功能性药物为代表的功能分子，赋予涂层不同的医用功能。In view of the deficiencies of the existing solutions stated above, the present invention aims to provide a preparation method of a degradable polycarbonate coating that reduces the corrosion rate of medical magnesium-based materials, and the coating has surface erosion degradation behavior. And compared with the polycarbonate without cross-linking, the degradation rate of the coating prepared by the present invention is significantly reduced and the anti-corrosion performance is significantly improved, and at the same time, it also has excellent scratch resistance, strong adhesion, good mechanical properties and excellent performance. of biocompatibility. In the preparation process of the coating of the present invention, functional molecules represented by functional drugs can be chemically bonded in the coating curing network through convenient chemical modification, so as to endow the coating with different medical functions.
本发明的目的通过如下手段来实现。The object of the present invention is achieved by the following means.
一种降低医用镁基材料腐蚀速率的快速固化可降解聚碳酸酯涂层的制备方法，采用如下步骤在镁基材料表面制备降低腐蚀速率的聚合物功能涂层：A preparation method of a fast-curing degradable polycarbonate coating that reduces the corrosion rate of medical magnesium-based materials, adopts the following steps to prepare a polymer functional coating that reduces the corrosion rate on the surface of the magnesium-based material:
S1以功能化六元环状碳酸酯单体作为投料单体，通过两种及以上单体的聚合反应制备分子量为1000～100000Da的可降解的聚碳酸酯共聚物；S1 uses the functionalized six-membered cyclic carbonate monomer as the feed monomer, and prepares a degradable polycarbonate copolymer with a molecular weight of 1000-100000 Da through the polymerization of two or more monomers;
S2将低生物毒性的交联剂(优选硫醇类交联剂)，与由S1制备得到的聚碳酸酯共聚物一起溶解在有机溶剂中，固含量为1～20wt％范围；S2 dissolves a low biological toxicity cross-linking agent (preferably a thiol cross-linking agent) together with the polycarbonate copolymer prepared by S1 in an organic solvent, and the solid content is in the range of 1-20wt%;
S3将S2制备得到的混合溶液涂覆在洁净的医用镁合金基材表面；并在涂层干燥后进行快速固化处理，最终得到功能涂层。S3 coats the mixed solution prepared by S2 on the surface of a clean medical magnesium alloy substrate; and performs rapid curing treatment after the coating is dried to finally obtain a functional coating.
具体地，第一步所述的功能化六元环状碳酸酯单体为：1,3-二氧杂环己烷-2-酮(TMC)、 5-甲基-5-烯丙氧基羰基-1,3-二恶烷-2-酮(MAC)、5-烯丙氧基-1,3-二恶烷-2-酮(ATMC)、 2-(甲基丙烯酰胺基)三亚甲基碳酸酯(MATC)5-甲基-5-丙烯酰氧基-1,3-二恶烷-2-酮(AC) 和5-甲基-5-甲基丙烯酰氧基-1,3-二恶烷-2-酮(MA)。具体结构如下所示：Specifically, the functionalized six-membered cyclic carbonate monomer described in the first step is: 1,3-dioxane-2-one (TMC), 5-methyl-5-allyloxy Carbonyl-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:
具体地，第一步制备得到的聚碳酸酯共聚物结构中侧基含有双键，如下面的结构式所示。Specifically, the side groups in the polycarbonate copolymer structure prepared in the first step contain double bonds, as shown in the following structural formula.
其中：in:
R1独立地选自H、CH3；R1 is independently selected from H, CH3 ;
R2独立地选自H、-OC(O)-CH2＝CH2、-NH-C(O)-CH(CH3)＝CH2、-O-CH2-CH＝CH2、 -COO-CH＝CH2和-OC(O)-C(CH3)＝CH2；R2 is independently selected from H, -OC(O)-CH2 =CH2 , -NH-C(O)-CH(CH3 )=CH2 , -O-CH2 -CH=CH2 , -COO -CH=CH2 and -OC(O)-C(CH3 )=CH2 ;
R3独立地选自H、CH3；R3 is independently selected from H, CH3 ;
R4独立地选自H、-OC(O)-CH2＝CH2、-NH-C(O)-CH(CH3)＝CH2、-O-CH2-CH＝CH2、 -COO-CH＝CH2和-OC(O)-C(CH3)＝CH2；R4 is independently selected from H, -OC(O)-CH2 =CH2 , -NH-C(O)-CH(CH3 )=CH2 , -O-CH2 -CH=CH2 , -COO -CH=CH2 and -OC(O)-C(CH3 )=CH2 ;
R2、R4不能同时为H；R2 and R4 cannot be H at the same time;
x、y为正整数，x+y<400。x and y are positive integers, and x+y<400.
具体地，S1所述的聚合反应为开环共聚，在无氧水条件下进行，其引发剂为含有一个羟基官能团的小分子或高分子，比如以苯甲醇，异丙醇为代表的含有一个羟基的小分子一元醇；催化剂为辛酸亚锡、DBU(二氮杂二环)、TBD(1,5,7-三氮杂二环[4.4.0]癸-5-烯)、MTBD (1-甲基-1,5,7-三氮杂二环[4.4.0]癸-5-烯)中的一种或几种。反应温度为20-160℃。Specifically, the polymerization reaction described in S1 is ring-opening copolymerization, which is carried out under the condition of oxygen-free water, and the initiator is a small molecule or macromolecule containing a hydroxyl functional group, such as benzyl alcohol, isopropanol, which contains a Small molecule monohydric alcohol of hydroxyl; catalysts are stannous octoate, DBU (diazabicyclo), TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene), MTBD (1 - one or more of methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene). The reaction temperature is 20-160°C.
具体地，S2所述的硫醇类交联剂为三羟甲基丙烷三(3-巯基丙酸酯)(TMPMP)、三羟甲基丙烷三(2-巯基乙酸酯)(TTMA)或季戊四醇四(3-巯基丙酸酯)(PETMP)以及二硫苏糖醇(DTT)；Specifically, the thiol crosslinking agent described in S2 is trimethylolpropane tris(3-mercaptopropionate) (TMPMP), trimethylolpropane tris(2-mercaptoacetate) (TTMA) or Pentaerythritol tetrakis(3-mercaptopropionate) (PETMP) and dithiothreitol (DTT);
更具体地，硫醇类交联剂中的硫醇与聚碳酸酯共聚物中的不饱和键的摩尔比例为9∶10 ～3∶2。More specifically, the molar ratio of the thiol in the thiol-based crosslinking agent to the unsaturated bond in the polycarbonate copolymer is 9:10 to 3:2.
更具体地，混合溶液中还添加助剂，所述助剂为引发剂、生物活性物质中的一种或两种；其中，引发剂为Irgacure 2959、丙酮酸乙酯和苯基-2,4,6-三甲基苯甲酰基膦酸锂(LAP)中的一种或几种；生物活性物质为RGD肽及2-甲基丙烯酰氧乙基磷酸胆碱(MPC)中的一种或两种；优选的，引发剂的含量为0-0.1wt％，生物活性物质含量为0-5wt％。More specifically, an auxiliary agent is also added in the mixed solution, and the auxiliary agent is one or both of an initiator and a biologically active substance; wherein, the initiator is Irgacure 2959, ethyl pyruvate and phenyl-2,4 , one or more of lithium 6-trimethylbenzoylphosphonate (LAP); biologically active substance is one or more of RGD peptide and 2-methacryloyloxyethylphosphorylcholine (MPC) Two; preferably, the content of the initiator is 0-0.1 wt %, and the content of the biologically active substance is 0-5 wt %.
具体地，第二步所述的有机溶剂为二氯甲烷、二甲亚砜、四氢呋喃或乙酸乙酯。Specifically, the organic solvent described in the second step is dichloromethane, dimethyl sulfoxide, tetrahydrofuran or ethyl acetate.
具体地，第三步所述的快速固化条件包括辐射、热或其组合。辐射包括UV光、电子束以及其它形式的光例如可见光、红外光和其它形式的电磁辐射。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.
本发明制备了一种通过“硫醇-烯”化学反应交联固化的可降解涂层。首先制备了具有烯基(或“烯”)官能团的聚碳酸酯共聚物其后通过添加多官能度硫醇作为交联剂，通过快速的自由基反应可以制备得到具有优异的防腐性能、良好的机械性能和附着力以及出色的耐刮擦性能的生物医用涂层。The present invention prepares a degradable coating that is cured by cross-linking through a "thiol-ene" chemical reaction. First, a polycarbonate copolymer with an alkenyl (or "ene") functional group was prepared. Then, by adding a multifunctional thiol as a cross-linking agent, a rapid free radical reaction can be used to prepare a polycarbonate copolymer with excellent anti-corrosion performance and good anti-corrosion properties. Biomedical coatings with mechanical properties and adhesion and excellent scratch resistance.
本发明有益的技术效果在于：The beneficial technical effects of the present invention are:
采用本发明方法制备得到的可降解聚碳酸酯涂层，能够有效降低医用镁基材料的腐蚀速率，提高其表面的生物相容性。由于其独特的表面溶蚀行为，会使其完全降解之前，一直很好的保护镁基材，阻止腐蚀介质与基材接触发生腐蚀；从根本上避免了常规的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。此外，本发明中涂层通过“硫醇-烯”化学交联解决了以聚三亚甲基碳酸酯为代表的表面溶蚀降解聚合物力学性能、表面硬度和耐磨性差的问题，同时仍然能够实现涂层的完全降解。还可以方便地在涂层交联网络中通过化学改性以功能性药物为代表的功能分子，赋予涂层不同的生物功能。The degradable polycarbonate coating prepared by the method of the invention can effectively reduce the corrosion rate of the medical magnesium-based material and improve the biocompatibility of its surface. Due to its unique surface corrosion behavior, the magnesium substrate has been well protected until it is completely degraded, preventing the corrosion of the corrosive medium from contacting the substrate; it fundamentally avoids conventional commercial polyester due to its bulk degradation mode. It has excellent long-term anti-corrosion performance to solve the problem of reducing the protective performance and even accelerating the corrosion of magnesium substrates caused by acidic degradation products. In addition, the coating in the present invention solves the problems of poor mechanical properties, surface hardness and wear resistance of the surface erosion degradation polymer represented by polytrimethylene carbonate through "thiol-ene" chemical cross-linking, while still achieving Complete degradation of the coating. It is also convenient to chemically modify functional molecules represented by functional drugs in the cross-linked network of the coating to endow the coating with different biological functions.
附图说明Description of drawings
图1为实施例1中的聚碳酸酯共聚物1的核磁共振氢谱。FIG. 1 is a hydrogen nuclear magnetic resonance spectrum of
图2为实施例1聚合物涂层材料在光固化前后的全反射红外谱图。FIG. 2 is the total reflection infrared spectrum of the polymer coating material of Example 1 before and after photocuring.
图3为测试例1中，裸镁合金以及实施例1-3和对比例1-2共六种样品，浸泡在37℃的人体模拟液(SBF)0、5、15、30天后，不同样品表面的扫描电子显微镜图片。Figure 3 shows the six samples of bare magnesium alloy, Examples 1-3 and Comparative Examples 1-2 in Test Example 1. After immersing in the human body simulation fluid (SBF) at 37°C for 0, 5, 15, and 30 days, the different samples Scanning electron microscope picture of the surface.
图4为测试例3中，裸镁合金、实施例1、实施例3、实施例5、对比例1和对比例2共六种样品，使用L929细胞在其表面培养24h和48小时之后，不同表面的细胞活力。Figure 4 shows that in Test Example 3, there are six samples of bare magnesium alloy, Example 1, Example 3, Example 5, Comparative Example 1 and Comparative Example 2. After culturing L929 cells on their surfaces for 24 hours and 48 hours, different Cell viability on the surface.
具体实施方式Detailed ways
以下结合具体实施案例对本发明作进一步的阐述。应理解，本发明不限于以下实施案例，所述方法如无特别说明均视为常规方法。所述材料如无特别说明均能从公开商业途径获得。The present invention will be further elaborated below in conjunction with specific implementation cases. It should be understood that the present invention is not limited to the following examples, and the methods are regarded as conventional methods unless otherwise specified. The materials are available from open commercial sources unless otherwise stated.
实施例1：Example 1:
(1)聚碳酸酯共聚物1的合成：使用苯甲醇作为引发剂，Sn(Oct)2作为催化剂，在100℃的甲苯溶液中进行聚合反应。将单体MAC(9.602g,48mmol)和TMC(3.267g,32mmol) 的混合物置于充分干燥的Schlenk装置中。将反应容器密封，抽真空并用氮气吹扫三次。接下来，在磁力搅拌下将甲苯(20mL)快速注入到Schlenk烧瓶中。在单体充分混合后，通过注射器加入苯甲醇的甲苯溶液(1.6mL,0.5M)和Sn(Oct)2甲苯溶液(4.8mL,0.1M)。将反应容器在磁力搅拌下置于100℃的油浴中。聚合24小时，通过旋转蒸发除去甲苯。将聚碳酸酯共聚物溶解在二氯甲烷中，沉淀到一定量的冷甲醇中，过滤分离，并在室温下真空干燥。通过核磁氢谱对聚碳酸酯共聚物的结果进行表征，结果如图1所示，从图中可以看出成功的合成了金属腐蚀预警聚合物涂层材料。(1) Synthesis of Polycarbonate Copolymer 1: Using benzyl alcohol as an initiator and Sn(Oct)2 as a catalyst, a polymerization reaction was carried out in a 100° C. toluene solution. A mixture of monomeric MAC (9.602 g, 48 mmol) and TMC (3.267 g, 32 mmol) was placed in a well dry Schlenk apparatus. The reaction vessel was sealed, evacuated and purged with nitrogen three times. Next, toluene (20 mL) was rapidly injected into the Schlenk flask with magnetic stirring. After the monomers were well mixed, benzyl alcohol in toluene (1.6 mL, 0.5 M) and Sn(Oct)2 in toluene (4.8 mL, 0.1 M) were added via syringe. The reaction vessel was placed in a 100°C oil bath with magnetic stirring. Polymerization was carried out for 24 hours and toluene was removed by rotary evaporation. The polycarbonate copolymer was dissolved in dichloromethane, precipitated into an amount of cold methanol, isolated by filtration, and dried in vacuo at room temperature. The results of the polycarbonate copolymers were characterized by hydrogen NMR. The results are shown in Figure 1. It can be seen from the figure that the metal corrosion early warning polymer coating material was successfully synthesized.
(2)可降解聚碳酸酯涂层的制备：聚碳酸酯共聚物1溶于CH2Cl2配置成20％(w/v)的浓度，搅拌2小时。然后，将聚碳酸酯共聚物1溶液与季戊四醇四(3-巯基丙酸酯)PETMP 混合，以使硫醇与烯烃的摩尔比例为1：1。并添加0.1wt％Irgacure I2959，将其溶解在溶液中。上述溶液浸涂在打磨清洗过的医用镁合金表面，并随后在室温下干燥3h。然后，通过30s的UV光照(365nm)最终形成硫醇-烯光交联涂层。图2显示了UV光照前后，基材表面聚合物膜的全反射红外光谱，UV光照前，基材表面存在硫醇基团和双键的红外吸收峰。光照后，二者的红外吸收峰消失，证明硫醇-烯反应成功进行，涂层实现了光固化。(2) Preparation of degradable polycarbonate coating:
实施例2：Example 2:
(1)聚碳酸酯共聚物2的合成：使用异丙醇作为引发剂，Sn(Oct)2作为催化剂，在80℃的二甲苯溶液中进行聚合反应。将单体MA(6.4g,32mmol)和TMC(4.9g,48mmol)的混合物置于充分干燥的Schlenk烧瓶中。将反应容器密封，抽真空并用氮气吹扫三次。接下来，在磁力搅拌下将甲苯(20mL)快速注入到Schlenk烧瓶中。在单体充分混合后，通过注射器加入异丙醇的甲苯溶液(1.6mL,0.5M)和Sn(Oct)2甲苯溶液(4.8mL,0.1M)。将反应容器在磁力搅拌下置于80℃的油浴中。聚合24小时，通过旋转蒸发除去甲苯。将聚碳酸酯共聚物2溶解在二氯甲烷中，沉淀到一定量的冷甲醇中，过滤分离，并在室温下真空干燥。(1) Synthesis of polycarbonate copolymer 2: Using isopropanol as an initiator and Sn(Oct)2 as a catalyst, the polymerization reaction was carried out in a xylene solution at 80°C. A mixture of monomeric MA (6.4 g, 32 mmol) and TMC (4.9 g, 48 mmol) was placed in a well-dried Schlenk flask. The reaction vessel was sealed, evacuated and purged with nitrogen three times. Next, toluene (20 mL) was rapidly injected into the Schlenk flask with magnetic stirring. After the monomers were well mixed, isopropanol in toluene (1.6 mL, 0.5 M) and Sn(Oct)2 in toluene (4.8 mL, 0.1 M) were added via syringe. The reaction vessel was placed in an oil bath at 80°C with magnetic stirring. Polymerization was carried out for 24 hours and toluene was removed by rotary evaporation.
(2)可降解聚碳酸酯涂层的制备：聚碳酸酯共聚物2溶于CH2Cl2配置成20％(w/v)的浓度，搅拌2小时。然后，将聚碳酸酯共聚物2溶液与三羟甲基丙烷三(3-巯基丙酸酯)(TMPMP)混合，以使硫醇与烯烃的摩尔比例为1：1。上述溶液浸涂在打磨清洗过的医用镁合金表面，并随后在室温下干燥3h。然后，通过电子束固化机(200kV)固化60s最终形成硫醇-烯电子束固化涂层。(2) Preparation of degradable polycarbonate coating:
实施例3：Example 3:
(1)聚碳酸酯共聚物3的合成：使用苯甲醇作为引发剂，1,8-二氮杂双环[5.4.0]十一碳-7- 烯(DBU)作为催化剂，在25℃的无水的二氯甲烷中进行聚合反应。将单体AC(9.4g,48mmol) 和TMC(3.267g,32mmol)的混合物置于充分干燥的Schlenk烧瓶中。将反应容器密封，抽真空并用氮气吹扫三次。在单体充分混合后，通过注射器加入苯甲醇的二氯甲烷溶液(1.6mL, 0.5M)和DBU二氯甲烷溶液(5mL,0.1M)。聚合24小时，将聚碳酸酯共聚物3溶液在冷甲醇中沉淀，过滤分离，并在室温下真空干燥。(1) Synthesis of polycarbonate copolymer 3: using benzyl alcohol as initiator and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst, at 25°C without The polymerization was carried out in water in dichloromethane. A mixture of monomer AC (9.4 g, 48 mmol) and TMC (3.267 g, 32 mmol) was placed in a well-dried Schlenk flask. The reaction vessel was sealed, evacuated and purged with nitrogen three times. After the monomers were well mixed, benzyl alcohol in dichloromethane (1.6 mL, 0.5 M) and DBU in dichloromethane (5 mL, 0.1 M) were added via syringe. After 24 hours of polymerization, the
(2)可降解聚碳酸酯涂层的制备：聚碳酸酯共聚物3溶于CH2Cl2配置成20％(w/v)的浓度，并在室温下以下搅拌2小时，然后，将聚碳酸酯共聚物3溶液与三羟甲基丙烷三(2-巯基乙酸酯)(TTMA)混合，以使硫醇与烯烃的摩尔比例为3∶2，并添加0.1wt％IrgacureI2959。上述溶液浸涂在打磨清洗过的医用镁合金表面，并随后在室温下干燥3h。然后，通过60s的UV光照(365nm)最终形成光交联涂层。(2) Preparation of degradable polycarbonate coating:
实施例4：Example 4:
(1)聚碳酸酯共聚物4的合成：使用苯甲醇作为引发剂，TBD(1,5,7-三氮杂二环[4.4.0] 癸-5-烯)作为催化剂，在25℃的无水的二氯甲烷中进行聚合反应。将单体MATC(2.9g,16 mmol)和TMC(6.27g,64mmol)的混合物置于充分干燥的Schlenk烧瓶中。将反应容器密封，抽真空并用氮气吹扫三次。在单体充分混合后，通过注射器加入苯甲醇的二氯甲烷溶液 (1.6mL,0.5M)和TBD二氯甲烷溶液(5mL,0.1M)。聚合24小时，将聚碳酸酯共聚物4 溶液在冷甲醇与水的混合溶液中沉淀，过滤分离，并在室温下真空干燥。(1) Synthesis of polycarbonate copolymer 4: using benzyl alcohol as initiator, TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) as catalyst, at 25°C The polymerization was carried out in anhydrous dichloromethane. A mixture of monomers MATC (2.9 g, 16 mmol) and TMC (6.27 g, 64 mmol) was placed in a well-dried Schlenk flask. The reaction vessel was sealed, evacuated and purged with nitrogen three times. After the monomers were well mixed, benzyl alcohol in dichloromethane (1.6 mL, 0.5 M) and TBD in dichloromethane (5 mL, 0.1 M) were added via syringe. After 24 hours of polymerization, the
(2)可降解聚碳酸酯涂层的制备：聚碳酸酯共聚物4溶于CH2Cl2配置成5％(w/v) 的浓度，并在室温下以下搅拌2小时，然后，将聚碳酸酯共聚物4溶液与二硫苏糖醇(DTT) 混合，以使硫醇与烯烃的摩尔比例为1∶1。上述溶液浸涂在打磨清洗过的医用镁合金表面，并随后在室温下干燥3h。然后，通过电子束固化机(200kV)固化60s最终形成电子束固化涂层。(2) Preparation of degradable polycarbonate coating:
实施例5：Example 5:
(1)聚碳酸酯共聚物5的合成：使用苯甲醇作为引发剂，Sn(Oct)2作为催化剂，在90℃的甲苯溶液中进行聚合反应。将单体ATMC(7.2g,48mmol)、MA(6.4g,32mmol)置于充分干燥的Schlenk装置中。将反应容器密封，抽真空并用氮气吹扫三次。接下来，在磁力搅拌下将甲苯(15mL)快速注入到Schlenk烧瓶中。在单体充分混合后，通过注射器加入苯甲醇的甲苯溶液(1.6mL,0.5M)和Sn(Oct)2甲苯溶液(4.8mL,0.1M)。将反应容器在磁力搅拌下置于90℃的油浴中。聚合24小时，通过旋转蒸发除去甲苯。将聚碳酸酯共聚物5溶解在二氯甲烷中，沉淀到一定量的冷甲醇中，过滤分离，并在室温下真空干燥。(1) Synthesis of polycarbonate copolymer 5: using benzyl alcohol as an initiator and Sn(Oct)2 as a catalyst, a polymerization reaction was carried out in a toluene solution at 90°C. Monomer ATMC (7.2 g, 48 mmol), MA (6.4 g, 32 mmol) were placed in a well dry Schlenk apparatus. The reaction vessel was sealed, evacuated and purged with nitrogen three times. Next, toluene (15 mL) was rapidly injected into the Schlenk flask with magnetic stirring. After the monomers were well mixed, benzyl alcohol in toluene (1.6 mL, 0.5 M) and Sn(Oct)2 in toluene (4.8 mL, 0.1 M) were added via syringe. The reaction vessel was placed in a 90°C oil bath with magnetic stirring. Polymerization was carried out for 24 hours and toluene was removed by rotary evaporation.
(2)可降解聚碳酸酯涂层的制备：聚碳酸酯共聚物5溶于溶于THF配置成10％(w/v)的浓度，搅拌2小时。然后，将聚碳酸酯聚合物5溶液与二硫苏糖醇(DTT)混合，以使硫醇与烯烃的摩尔比例为9：10。并添加0.1wt％Irgacure I2959，以及5wt％的生物活性物资 RGD肽并将其溶解在溶液中。上述溶液浸涂在打磨清洗过的医用镁合金表面，并随后在室温下干燥3h。然后，通过30s的UV光照(365nm)最终形成硫醇-烯光交联生物活性涂层。(2) Preparation of degradable polycarbonate coating:
对比例1：Comparative Example 1:
将商品化PTMC聚合物，配置成浓度为10wt％的二氯甲烷溶液，浸涂在打磨清洗过的医用镁合金表面，并随后在室温下干燥24h。对比例1是一种常用的表面溶蚀性降解聚合物，被应用于中国专利CN102327862B中。A commercial PTMC polymer was prepared into a dichloromethane solution with a concentration of 10 wt %, dip-coated on the surface of the polished and cleaned medical magnesium alloy, and then dried at room temperature for 24 h. Comparative Example 1 is a commonly used surface erosion degradable polymer, which is used in Chinese patent CN102327862B.
对比例2：Comparative Example 2:
将商品化PLLA聚合物，配置成浓度为10wt％的THF溶液，浸涂在打磨清洗过的医用镁合金表面，并随后在室温下干燥24h。对比例2是一种能够应用于医用镁合金防腐的可降解聚合物涂层(中国专利CN 109161882A)，作为一种可降解聚酯，PLLA降解行为为本体溶蚀降解。The commercial PLLA polymer was prepared into a THF solution with a concentration of 10 wt %, dip-coated on the surface of the polished and cleaned medical magnesium alloy, and then dried at room temperature for 24 h. Comparative Example 2 is a degradable polymer coating that can be applied to medical magnesium alloy anticorrosion (Chinese patent CN 109161882A). As a degradable polyester, the degradation behavior of PLLA is bulk corrosion degradation.
测试例1Test Example 1
用于测试实施例与对比例处理后镁合金表面的耐蚀性。It is used to test the corrosion resistance of the magnesium alloy surface treated by the examples and the comparative examples.
测试方法为：将未经处理的裸镁合金，实施例1-5以及对比例1-2制备得到的样品(厚度保持一致约10μm)，分别浸没于SBF(人体模拟液)中，然后在在37±0.5℃的水浴中浸泡 30天。浸泡期间，每隔2天更换一次SBF。通过测试浸泡前后样品的重量损失判断样品的耐蚀性，如表1所示。The test method is as follows: immerse the untreated bare magnesium alloy, the samples prepared in Examples 1-5 and Comparative Examples 1-2 (the thickness is about 10 μm), respectively, in SBF (human body simulation fluid), and then in the Soak in a water bath at 37±0.5°C for 30 days. During immersion, replace the SBF every 2 days. The corrosion resistance of the samples was judged by testing the weight loss of the samples before and after soaking, as shown in Table 1.
表2 浸泡前后样品的重量损失Table 2 Weight loss of samples before and after soaking
从实施例1-5的结果来看，相对于裸镁合金，实施例1-5所得的可降解涂层能够在30天的浸泡后，质量损失率低于6％，说明它们的可降解涂层具有非常优异的防腐性能，使基材在浸泡后保持高度完整。而对比例1在浸泡30天后，质量损失接近50％，甚至比没有涂层的裸镁样品还高，这是由于其酸性的降解产物进一步加速了基材的腐蚀和降解。对比例2的质量损失明显小于裸镁合金，但是也显著大于实施例1-5得到的结果，说明了实施例1-5防腐性能明显优于对比例2，这是因为固化形成的交联网络能够降低涂层的降解速率，更有效地隔绝腐蚀介质对镁基材的侵蚀。From the results of Examples 1-5, compared with the bare magnesium alloys, the degradable coatings obtained in Examples 1-5 can have a mass loss rate of less than 6% after 30 days of immersion, indicating that their degradable coatings The layer has very good corrosion protection properties, keeping the substrate highly intact after soaking. In contrast, after immersion for 30 days, the mass loss of Comparative Example 1 was close to 50%, which was even higher than that of the uncoated bare magnesium sample, because its acidic degradation products further accelerated the corrosion and degradation of the substrate. The mass loss of Comparative Example 2 is significantly smaller than that of the bare magnesium alloy, but it is also significantly greater than the results obtained in Examples 1-5, indicating that the anti-corrosion performance of Examples 1-5 is significantly better than that of Comparative Example 2, because the cross-linked network formed by curing It can reduce the degradation rate of the coating and more effectively isolate the erosion of the corrosive medium to the magnesium substrate.
测试例2：Test case 2:
用于测试实施例与对比例处理后镁合金表面的耐蚀性。It is used to test the corrosion resistance of the magnesium alloy surface treated by the examples and the comparative examples.
测试方法为：将未经处理的裸镁合金，实施例1-3以及对比例1-2制备得到的样品(厚度保持一致约10μm)，分别浸没于SBF(人体模拟液)中，然后在在37±0.5℃的水浴中浸泡30天。浸泡期间，每隔2天更换一次SBF。通过FE-SEM观察样品在5天、15天以及 20天的表面形貌，如图3所示。The test method is: immerse the untreated bare magnesium alloy, the samples prepared in Examples 1-3 and Comparative Examples 1-2 (the thickness is about 10 μm), respectively, in SBF (human body simulation fluid), and then in the Soak in a water bath at 37±0.5°C for 30 days. During immersion, replace the SBF every 2 days. The surface morphologies of the samples at 5 days, 15 days and 20 days were observed by FE-SEM, as shown in Figure 3.
从实施例1-3的结果来看，相对于裸镁合金，实施例1-3所得的可降解涂层能够在30天内(涂层完全降解前)保持完整的形貌，因此始终可以隔绝基材与腐蚀介质，实现对基材的长效保护。而对比例1在浸泡15天后，样品表面已经出现腐蚀产生的裂纹，说明虽然对比例 1和实施例1-3一样都是表面溶蚀的降解行为，但是防腐效果明显不如实施例1-3。对比例2 在浸泡5天时候涂层表面就出现了微孔，15天时微孔变大且布满整个表面，30天后完全降解且基材表面出现大块裂缝。因此测试结果表明实施例1-3防腐性能明显优于对比例1-2。From the results of Examples 1-3, compared with the bare magnesium alloy, the degradable coatings obtained in Examples 1-3 can maintain a complete morphology within 30 days (before the coating is completely degraded), so it can always isolate the base materials and corrosive media to achieve long-term protection of the substrate. And comparative example 1 after immersion for 15 days, the sample surface has already appeared the crack that corrosion produces, shows that although comparative example 1 and embodiment 1-3 are the same as the degradation behavior of surface corrosion, but the anti-corrosion effect is obviously inferior to embodiment 1-3. Comparative Example 2 Micropores appeared on the coating surface after 5 days of immersion, and the micropores became larger and covered the entire surface at 15 days. After 30 days, the coating was completely degraded and large cracks appeared on the surface of the substrate. Therefore, the test results show that the anti-corrosion performance of Example 1-3 is significantly better than that of Comparative Example 1-2.
测试例3：Test case 3:
用于测试实施例与对比例中镁合金表面制备得到涂层的基本性能。It is used to test the basic properties of the coatings prepared on the surface of magnesium alloys in the examples and comparative examples.
测试方法为：对实施例1-5以及对比例1-2采用国标GB/T 9286-1998测试涂层的附着力；采用国标GB/T 6739-2006测试涂层的铅笔硬度。使用膜厚仪测试涂层的厚度。如表2所示：The test methods are as follows: the national standard GB/T 9286-1998 is used to test the adhesion of the coatings for Examples 1-5 and Comparative Examples 1-2; the pencil hardness of the coatings is tested by the national standard GB/T 6739-2006. Use a film thickness gauge to test the thickness of the coating. As shown in table 2:
表2 涂层的基本性能测试结果Table 2 Test results of basic properties of coatings
从测试结果来看实施例1-3具有较高的铅笔硬度和优异的附着力，性能明显优于两个对比例。说明本发明在涂层的基本性能上有明显优势。From the test results, Examples 1-3 have higher pencil hardness and excellent adhesion, and the performance is obviously better than the two comparative examples. It shows that the present invention has obvious advantages in the basic performance of the coating.
测试例4：Test example 4:
用于测试实施例与对比例处理后镁合金表面的细胞活性。It is used to test the cell viability on the magnesium alloy surface after the treatment of the example and the comparative example.
测试方法为：首先将裸镁合金样品、实施例1,3,5及对比例1-2进行紫外光照灭菌。将 L929细胞以每孔6.0×104个细胞的浓度接种在它们的表面上。接种后，将L929细胞在含有 10％胎牛血清和1％抗生素的培养基中培养(37℃、5％的CO2浓度的潮湿气氛中)。培养24小时和48小时后，通过MTT测试不同样品的细胞活性。如图4所示：The test method is as follows: first, the bare magnesium alloy samples, Examples 1, 3, 5 and Comparative Examples 1-2 are sterilized by ultraviolet light. L929 cells were seededon their surfaces at a concentration of 6.0 x 104 cells per well. After inoculation, L929 cells were cultured in medium containing 10% fetal bovine serum and 1% antibiotics (37°C in a humidified atmosphere with a CO2 concentration of 5%). Different samples were tested for cell viability by MTT after 24 and 48 hours of culture. As shown in Figure 4:
从测试结果来看，在细胞培养24h后，实施例和对比例中的涂层样品都有相似的细胞活性，然而持续培养48h后，由于实施例1,3,5样品良好的防腐性能和降解产物为无毒的二氧化碳和水，其细胞活力远远优于对比例1-2。说明本发明制备得到的生物功能涂层具有更加优异的细胞相容性。From the test results, after 24 hours of cell culture, the coating samples in the examples and comparative examples have similar cell activity, but after 48 hours of continuous culture, due to the good antiseptic properties and degradation of the samples in Examples 1, 3, and 5 The product is non-toxic carbon dioxide and water, and its cell viability is much better than that of Comparative Examples 1-2. It shows that the biological functional coating prepared by the present invention has more excellent cytocompatibility.
所述仅是本发明的优选实施方式，应当指出：对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。What is described is only the preferred embodiment of the present invention, it should be pointed out that: for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can also be made, and these improvements and modifications should also be It is regarded as the protection scope of the present invention.
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