技术领域Technical Field
本发明属于硅水凝胶材料领域，具体涉及一种具有抑菌功能的硅水凝胶材料及其制备方法和应用。The invention belongs to the field of silicone hydrogel materials, and in particular relates to a silicone hydrogel material with antibacterial function and a preparation method and application thereof.
背景技术Background Art
传统水凝胶角膜接触镜是由亲水性单体如甲基丙烯酸羟基乙酯，N-乙烯基吡咯烷酮等共聚而成的，普遍存在着透氧率较低，长期配戴会造成角膜缺氧，从而导致眼干、结膜充血、角膜水肿等眼表问题。Traditional hydrogel corneal contact lenses are copolymerized with hydrophilic monomers such as hydroxyethyl methacrylate and N-vinyl pyrrolidone. They generally have low oxygen permeability. Long-term wearing can cause corneal hypoxia, leading to ocular surface problems such as dry eyes, conjunctival congestion, and corneal edema.
硅水凝胶是将有机硅结构单元引入到水凝胶中得到的材料，结合了有机硅的高透氧性和水凝胶的柔软性特点，拥有比水凝胶更高的氧气透过能力，近些年来用作角膜接触镜的材料之一。对于长时间配戴角膜接触镜者及容易眼干者，硅水凝胶角膜接触镜有着巨大的优势。近几年角膜接触镜市场快速从水凝胶向硅水凝胶转变，目前全球市场大约半数以上的角膜接触镜为硅水凝胶镜片。Silicone hydrogel is a material obtained by introducing silicone structural units into hydrogel. It combines the high oxygen permeability of silicone and the softness of hydrogel. It has a higher oxygen permeability than hydrogel. In recent years, it has been used as one of the materials for corneal contact lenses. For those who wear corneal contact lenses for a long time and those who are prone to dry eyes, silicone hydrogel corneal contact lenses have huge advantages. In recent years, the corneal contact lens market has rapidly shifted from hydrogel to silicone hydrogel. Currently, more than half of the corneal contact lenses in the global market are silicone hydrogel lenses.
但是，由于角膜接触镜者涉及到手接触、长时间暴露在空气里以及与人体组织直接接触，容易造成细菌或其它微生物在其表面积聚现象，进而诱发眼部疾病。比如，急性卡他性结膜炎，俗称红眼病，就是一种由细菌感染引起的常见急性流行性眼病。常见的致病菌包括金黄色葡萄球菌、链球菌和铜绿假单胞菌等。因此，如何在佩戴角膜接触镜中避免上述问题将对角膜接触镜的进一步推广有着重要意义。常见的护理手段就是佩戴结束后将角膜接触镜浸泡在镜片护理液中，利用后者中含有的少量抗菌剂如季铵盐类表面活性剂等，对镜片表面进行消毒、清洗。由此可以看出，如能制备出具有抗菌功能的镜片，直接抑制细菌在其表面生长，将可以从根本上克服角膜接触镜表面易繁殖细菌或其他微生物现象。However, since contact lenses involve hand contact, long-term exposure to the air, and direct contact with human tissue, it is easy for bacteria or other microorganisms to accumulate on their surfaces, thereby inducing eye diseases. For example, acute catarrhal conjunctivitis, commonly known as pink eye, is a common acute epidemic eye disease caused by bacterial infection. Common pathogenic bacteria include Staphylococcus aureus, Streptococcus, and Pseudomonas aeruginosa. Therefore, how to avoid the above problems when wearing contact lenses will be of great significance to the further promotion of contact lenses. A common nursing method is to soak the contact lenses in lens care solution after wearing, and use a small amount of antibacterial agents such as quaternary ammonium surfactants contained in the latter to disinfect and clean the lens surface. It can be seen from this that if a lens with antibacterial function can be prepared to directly inhibit the growth of bacteria on its surface, it will be possible to fundamentally overcome the phenomenon that bacteria or other microorganisms are easy to breed on the surface of the contact lens.
因此，开发一种有效的抑菌活性成分，能够用于制备兼具透氧性和抑菌性的硅水凝胶镜片，是本领域技术人员亟待解决的技术问题之一。Therefore, developing an effective antibacterial active ingredient that can be used to prepare silicone hydrogel lenses with both oxygen permeability and antibacterial properties is one of the technical problems that technical personnel in this field urgently need to solve.
发明内容Summary of the invention
本发明的第一目的在于提供一种具有抑菌功能的硅水凝胶材料，所述硅水凝胶材料由以下重量百分比的原料组成：三甲氧基（3-甲氧基丙基）硅烷5-10%、四甲氧基硅烷10-15%、甘油5-7%、抗菌材料0.2-0.5%、余量水。The first object of the present invention is to provide a silicone hydrogel material with antibacterial function, wherein the silicone hydrogel material is composed of the following raw materials in weight percentage: 5-10% trimethoxy (3-methoxypropyl) silane, 10-15% tetramethoxy silane, 5-7% glycerol, 0.2-0.5% antibacterial material, and the remainder water.
进一步地，所述抗菌材料的制备方法如下：Furthermore, the preparation method of the antibacterial material is as follows:
（1）向聚磷酸中加入2-三氟甲基苯胺和4,4,4-三氟乙酰乙酸乙酯，搅拌反应，反应结束后，将反应液倒入水中，析出沉淀，收集沉淀并进行洗涤、干燥，得到中间体1；(1) adding 2-trifluoromethylaniline and ethyl 4,4,4-trifluoroacetoacetate to polyphosphoric acid, stirring for reaction, and after the reaction is completed, pouring the reaction solution into water to precipitate, collecting the precipitate, washing, and drying to obtain intermediate 1;
（2）向中间体1的溶液中加入氯化亚砜，于55-60℃搅拌5-8h；然后将温度降至室温，向反应液中加入氨水继续反应，反应结束后，反应液经纯化得到中间体2；(2) Add thionyl chloride to the solution of intermediate 1 and stir at 55-60°C for 5-8h; then lower the temperature to room temperature and add ammonia water to the reaction solution to continue the reaction. After the reaction is completed, purify the reaction solution to obtain intermediate 2;
（3）将中间体2和3-氰基苯异氰酸酯加入溶剂中进行反应，反应结束后，过滤，收集沉淀并进行洗涤、干燥，得到中间体3；(3) adding intermediate 2 and 3-cyanophenyl isocyanate to a solvent for reaction. After the reaction is completed, filtering, collecting the precipitate, washing, and drying to obtain intermediate 3;
（4）向中间体3的溶液中加入3,4-二羟基苯甲醛，搅拌反应，反应结束后，反应液经后处理得到中间体4；(4) adding 3,4-dihydroxybenzaldehyde to the solution of intermediate 3 and stirring for reaction. After the reaction is completed, the reaction solution is post-treated to obtain intermediate 4;
（5）向聚赖氨酸的水溶液中加入3-醛基苯硼酸，搅拌反应，反应结束后，向反应液中加入乙醇，收集沉淀物并进行洗涤、干燥，得到中间体5；(5) adding 3-formylphenylboronic acid to the aqueous solution of polylysine and stirring to react. After the reaction is completed, adding ethanol to the reaction solution, collecting the precipitate, washing it, and drying it to obtain an intermediate 5;
（6）将所述中间体4和所述中间体5加到混合溶剂中进行反应，反应结束后，反应液经透析、冷冻干燥，得到所述抗菌材料。(6) The intermediate 4 and the intermediate 5 are added to a mixed solvent for reaction. After the reaction is completed, the reaction solution is dialyzed and freeze-dried to obtain the antibacterial material.
进一步地，步骤（1）中所述2-三氟甲基苯胺、4,4,4-三氟乙酰乙酸乙酯和聚磷酸的摩尔比为（1.0-1.5）:1:（8.2-9.0），所述搅拌反应的时间为3-6 h，搅拌反应的温度为150-180℃。Furthermore, in step (1), the molar ratio of 2-trifluoromethylaniline, 4,4,4-trifluoroacetoacetic acid ethyl ester and polyphosphoric acid is (1.0-1.5):1:(8.2-9.0), the stirring reaction time is 3-6 h, and the stirring reaction temperature is 150-180°C.
进一步地，步骤（2）中所述中间体1、氯化亚砜和氨水的用量比为1 mmol:（1-1.5）mmol：(4-5) mL；所述反应的温度为55-60℃，反应的时间为5-8 h。Furthermore, in step (2), the ratio of the intermediate 1, thionyl chloride and aqueous ammonia is 1 mmol: (1-1.5) mmol: (4-5) mL; the reaction temperature is 55-60° C., and the reaction time is 5-8 h.
进一步地，步骤（3）中所述中间体2和3-氰基苯异氰酸酯的的摩尔比为1:（1-1.5），所述反应的温度为110-120℃，反应的时间为1-2 h。Furthermore, in step (3), the molar ratio of the intermediate 2 to 3-cyanophenyl isocyanate is 1:(1-1.5), the reaction temperature is 110-120° C., and the reaction time is 1-2 h.
进一步地，步骤（4）中所述中间体3和3,4二羟基苯甲醛的摩尔比为1:（1.2-2）；所述搅拌反应的时间为12-15 h；所述后处理的过程为：将反应液浓缩、干燥后进行柱层析分离。Furthermore, in step (4), the molar ratio of the intermediate 3 to 3,4-dihydroxybenzaldehyde is 1:(1.2-2); the stirring reaction time is 12-15 h; and the post-treatment process is: concentrating and drying the reaction solution and then performing column chromatography separation.
进一步地，以聚赖氨酸单体计，步骤（5）中所述聚赖氨酸单体与3-醛基苯硼酸的摩尔比为（10-12）:（3-4），所述搅拌反应的时间为12-15 h。Furthermore, based on the polylysine monomer, the molar ratio of the polylysine monomer to 3-formylphenylboronic acid in step (5) is (10-12):(3-4), and the stirring reaction time is 12-15 h.
进一步地，步骤（6）中所述中间体4和中间体5的摩尔比为1:（1-1.5），所述混合溶剂为体积比为1:1的乙醇和水的混合液；所述反应的时间为8-12 h。Furthermore, in step (6), the molar ratio of intermediate 4 to intermediate 5 is 1:(1-1.5), the mixed solvent is a mixture of ethanol and water in a volume ratio of 1:1; and the reaction time is 8-12 h.
本发明的第二目的在于提供一种具有抑菌功能的硅水凝胶材料的制备方法，按配方量称取三甲氧基（3-甲氧基丙基）硅烷、四甲氧基硅烷、甘油、抗菌材料和水混合均匀，于室温下进行交联反应，得到所述具有抑菌功能的硅水凝胶材料。The second object of the present invention is to provide a method for preparing a silicone hydrogel material with antibacterial function, wherein trimethoxy (3-methoxypropyl) silane, tetramethoxy silane, glycerol, an antibacterial material and water are weighed according to the formula amount, mixed evenly, and a cross-linking reaction is carried out at room temperature to obtain the silicone hydrogel material with antibacterial function.
本发明的第三目的在于提供一种上述具有抑菌功能的硅水凝胶材料在制备角膜接触镜中的应用。The third object of the present invention is to provide an application of the above-mentioned silicone hydrogel material with antibacterial function in the preparation of corneal contact lenses.
与现有技术相比，本发明的有益效果主要在于：Compared with the prior art, the beneficial effects of the present invention are mainly:
本发明通过对聚赖氨酸进行化学改性，制备了结构新颖的抗菌材料，将所述抗菌材料与硅水凝胶基体进行凝胶化，制得了具有优良抗菌性能的硅水凝胶材料，该硅水凝胶材料能够有效抑制包括大肠杆菌、金黄色葡萄球菌和铜绿假单胞菌的生长。此外，本发明制备的具有抑菌功能的硅水凝胶材料还具有良好的细胞相容性和亲水性。The present invention prepares an antibacterial material with a novel structure by chemically modifying polylysine, and gelates the antibacterial material with a silicone hydrogel matrix to obtain a silicone hydrogel material with excellent antibacterial properties. The silicone hydrogel material can effectively inhibit the growth of Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. In addition, the silicone hydrogel material with antibacterial function prepared by the present invention also has good cell compatibility and hydrophilicity.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1为本发明抗菌材料的合成路线图；FIG1 is a synthetic route diagram of the antibacterial material of the present invention;
图2为本发明实施例1和对比例1硅水凝胶的SEM图；FIG2 is a SEM image of the silicone hydrogel of Example 1 of the present invention and Comparative Example 1;
图3为本发明各组硅水凝胶的杀菌率结果图；FIG3 is a graph showing the sterilization rate of each group of silicone hydrogels of the present invention;
图4为本发明各组硅水凝胶的细胞存活率。FIG. 4 shows the cell survival rates of various groups of silicone hydrogels of the present invention.
具体实施方式DETAILED DESCRIPTION
以下结合具体实施例、对比例、试验例对本发明的技术方案做进一步的解释说明。The technical solution of the present invention is further explained below in conjunction with specific embodiments, comparative examples and test examples.
以下实施例、对比例、试验例中，采用的原料和制备方法如无特别说明，均为本领域常规的材料和技术。In the following examples, comparative examples and test examples, the raw materials and preparation methods used are conventional materials and techniques in the art unless otherwise specified.
实施例1Example 1
一种具有抑菌功能的硅水凝胶材料，由以下重量百分比的原料组成：三甲氧基（3-甲氧基丙基）硅烷5%、四甲氧基硅烷10%、甘油5%、抗菌材料0.2%、余量水。具体的制备步骤如下：A silicone hydrogel material with antibacterial function is composed of the following raw materials in weight percentage: 5% trimethoxy (3-methoxypropyl) silane, 10% tetramethoxy silane, 5% glycerol, 0.2% antibacterial material, and the balance water. The specific preparation steps are as follows:
S1，制备抗菌材料，其合成路线如图1所示：S1, prepare antibacterial material, the synthesis route of which is shown in Figure 1:
（1）向聚磷酸（637.7 mmol）中加入2-三氟甲基苯胺（77.6 mmol）和4,4,4-三氟乙酰乙酸乙酯（77.7 mmol）混合均匀，将混合物在150oC下搅拌3小时，通过TLC监测反应。反应结束后，在剧烈搅拌下将反应液缓慢倒入300 mL冰冷的蒸馏水中，形成沉淀。收集沉淀物并用冷蒸馏水洗涤，得到91%收率的中间体1。(1) Add 2-trifluoromethylaniline (77.6 mmol) and ethyl 4,4,4-trifluoroacetoacetate (77.7 mmol) to polyphosphoric acid (637.7 mmol) and mix well. Stir the mixture at 150° C for 3 hours and monitor the reaction by TLC. After the reaction, the reaction solution was slowly poured into 300 mL of ice-cold distilled water under vigorous stirring to form a precipitate. The precipitate was collected and washed with cold distilled water to obtain intermediate 1 with a yield of 91%.
（2）将中间体1（5 mmol）溶于100 mL干燥的DMF中，并向其中加入氯化亚砜（5mmol），在55℃条件下搅拌反应5 h；降温至室温，然后向反应液中滴加质量浓度为37 %的氨水4 mL，继续反应2 h；反应结束后，将反应液进行浓缩、干燥和柱层析分离，得到中间体2；(2) The intermediate 1 (5 mmol) was dissolved in 100 mL of dry DMF, and thionyl chloride (5 mmol) was added thereto, and the reaction was stirred at 55°C for 5 h. The reaction solution was cooled to room temperature, and then 4 mL of 37% ammonia water was added dropwise to the reaction solution, and the reaction was continued for 2 h. After the reaction was completed, the reaction solution was concentrated, dried and separated by column chromatography to obtain the intermediate 2.
（3）将中间体2（10 mmol）和3-氰基苯异氰酸酯（10 mmol）加入到150 mL无水甲苯中，110℃条件下搅拌1 h，利用TLC监测反应情况。反应结束后，过滤反应液，收集沉淀并用正己烷进行洗涤，干燥后得到中间体3。(3) Intermediate 2 (10 mmol) and 3-cyanophenyl isocyanate (10 mmol) were added to 150 mL of anhydrous toluene and stirred at 110°C for 1 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was filtered, and the precipitate was collected and washed with n-hexane, and then dried to obtain intermediate 3.
（4）将中间体3（10 mmol）加至100 mL二甲基亚砜中，并向其中加入3,4二羟基苯甲醛（12 mmol），搅拌反应15 h；反应结束后，将反应液浓缩、干燥、过柱纯化得到中间体4；(4) Add intermediate 3 (10 mmol) to 100 mL of dimethyl sulfoxide, and add 3,4-dihydroxybenzaldehyde (12 mmol) thereto, and stir to react for 15 h. After the reaction, concentrate the reaction solution, dry it, and purify it by column to obtain intermediate 4.
（5）将聚赖氨酸（10 mmol，以单体计算）溶于100 mL去离子在水中，并使用NaHCO3(1M)将pH调节至8.2，向其中加入3-醛基苯硼酸（3 mmol），搅拌反应12 h；反应结束后，向反应液中加入乙醇，收集析出的沉淀并用乙醇洗涤，干燥后即可得到中间体5；(5) Dissolve polylysine (10 mmol, calculated as monomer) in 100 mL of deionized water, adjust the pH to 8.2 with NaHCO3 (1 M), add 3-formylphenylboronic acid (3 mmol), and stir for 12 h. After the reaction, add ethanol to the reaction solution, collect the precipitate, wash it with ethanol, and dry it to obtain intermediate 5.
（6）将中间体4（10 mmol）和中间体5（10 mmol，以赖氨酸单体算）加入到乙醇和水（体积比为1:1）中，搅拌反应8 h后，反应液用超纯水透析3 d（透析袋的截留分子量为2000Da），冷冻干燥后即可得到抗菌材料。(6) Intermediate 4 (10 mmol) and intermediate 5 (10 mmol, calculated as lysine monomer) were added to ethanol and water (volume ratio of 1:1). After stirring for 8 h, the reaction solution was dialyzed against ultrapure water for 3 d (the molecular weight cutoff of the dialysis bag was 2000 Da) and freeze-dried to obtain the antibacterial material.
S2，制备硅水凝胶材料：S2, preparation of silicone hydrogel material:
将三甲氧基（3-甲氧基丙基）硅烷、四甲氧基硅烷、甘油、上述抗菌材料和水按配方量混合均匀，将混合物倒入角膜接触镜模具中，在室温下放置数小时，使其进行自然交联反应，形成硅水凝胶，即所述具有抑菌功能的硅水凝胶材料。Trimethoxy (3-methoxypropyl) silane, tetramethoxysilane, glycerol, the above antibacterial materials and water are mixed evenly according to the formula amount, and the mixture is poured into a corneal contact lens mold and left at room temperature for several hours to allow it to undergo a natural cross-linking reaction to form a silicone hydrogel, i.e., the silicone hydrogel material with antibacterial function.
实施例2Example 2
一种具有抑菌功能的硅水凝胶材料，由以下重量百分比的原料组成：三甲氧基（3-甲氧基丙基）硅烷8%、四甲氧基硅烷12%、甘油6%、抗菌材料0.4%、余量水。具体的制备步骤如下：A silicone hydrogel material with antibacterial function is composed of the following raw materials in percentage by weight: 8% trimethoxy (3-methoxypropyl) silane, 12% tetramethoxy silane, 6% glycerol, 0.4% antibacterial material, and the balance water. The specific preparation steps are as follows:
S1，制备抗菌材料，其合成路线如图1所示：S1, prepare antibacterial material, the synthesis route of which is shown in Figure 1:
（1）向聚磷酸（660.45 mmol）中加入2-三氟甲基苯胺（93.2 mmol）和4,4,4-三氟乙酰乙酸乙酯（77.7 mmol）混合均匀，将混合物在160oC下搅拌5小时，通过TLC监测反应。反应结束后，在剧烈搅拌下将反应液缓慢倒入300 mL冰冷的蒸馏水中，形成沉淀。收集沉淀物并用冷蒸馏水洗涤，得到中间体1。(1) Add 2-trifluoromethylaniline (93.2 mmol) and ethyl 4,4,4-trifluoroacetoacetate (77.7 mmol) to polyphosphoric acid (660.45 mmol) and mix well. Stir the mixture at 160° C for 5 hours and monitor the reaction by TLC. After the reaction is completed, the reaction solution is slowly poured into 300 mL of ice-cold distilled water under vigorous stirring to form a precipitate. Collect the precipitate and wash it with cold distilled water to obtain intermediate 1.
（2）将中间体1（5 mmol）溶于100 mL干燥的DMF中，并向其中加入氯化亚砜（6mmol），在60℃条件下搅拌6 h；降温至室温，然后向反应液中滴加质量浓度为37 %的氨水5mL，继续反应4 h；反应结束后，将反应液进行浓缩、干燥和柱层析分离，得到中间体2。(2) Intermediate 1 (5 mmol) was dissolved in 100 mL of dry DMF, and thionyl chloride (6 mmol) was added thereto. The mixture was stirred at 60 °C for 6 h. The mixture was cooled to room temperature, and 5 mL of 37% aqueous ammonia was added dropwise to the reaction solution. The reaction was continued for 4 h. After the reaction was completed, the reaction solution was concentrated, dried and separated by column chromatography to obtain intermediate 2.
（3）将中间体2（10 mmol）和3-氰基苯异氰酸酯（12 mmol）加入到150 mL无水甲苯中，120℃条件下搅拌1.5 h，利用TLC监测反应情况。反应结束后，过滤反应液，收集沉淀并用正己烷进行洗涤，干燥后得到中间体3。(3) Intermediate 2 (10 mmol) and 3-cyanophenyl isocyanate (12 mmol) were added to 150 mL of anhydrous toluene and stirred at 120°C for 1.5 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was filtered, and the precipitate was collected and washed with n-hexane, and then dried to obtain intermediate 3.
（4）将中间体3（10 mmol）加至100 mL二甲基亚砜中，并向其中加入3,4二羟基苯甲醛（15 mmol），搅拌反应13 h；反应结束后，将反应液浓缩、干燥、过柱纯化得到中间体4；(4) Add intermediate 3 (10 mmol) to 100 mL of dimethyl sulfoxide, and add 3,4-dihydroxybenzaldehyde (15 mmol) thereto, and stir to react for 13 h. After the reaction, concentrate the reaction solution, dry it, and purify it by column to obtain intermediate 4.
（5）将聚赖氨酸（12 mmol，以单体计算）溶于100 mL去离子在水中，并使用NaHCO3(1M)将pH调节至8.2，向其中加入3-醛基苯硼酸（3 mmol），搅拌反应14 h；反应结束后，向反应液中加入乙醇，收集析出的沉淀并用乙醇洗涤，干燥后即可得到中间体5；(5) Dissolve polylysine (12 mmol, calculated as monomer) in 100 mL of deionized water, adjust the pH to 8.2 with NaHCO3 (1 M), add 3-formylphenylboronic acid (3 mmol), and stir for 14 h. After the reaction, add ethanol to the reaction solution, collect the precipitate, wash it with ethanol, and dry it to obtain intermediate 5.
（6）将中间体4（10 mmol）和中间体5（12 mmol，以赖氨酸单体算）加入到乙醇和水（体积比为1:1）中，搅拌反应10 h后，反应液用超纯水透析3 d（透析袋的截留分子量为2000Da），冷冻干燥后即可得到抗菌材料。(6) Intermediate 4 (10 mmol) and intermediate 5 (12 mmol, calculated as lysine monomer) were added to ethanol and water (volume ratio of 1:1). After stirring for 10 h, the reaction solution was dialyzed against ultrapure water for 3 d (the molecular weight cutoff of the dialysis bag was 2000 Da) and freeze-dried to obtain the antibacterial material.
S2，制备硅水凝胶材料：S2, preparation of silicone hydrogel material:
将三甲氧基（3-甲氧基丙基）硅烷、四甲氧基硅烷、甘油、上述抗菌材料和水按配方量混合均匀，将混合物倒入角膜接触镜模具中，在室温下放置数小时，使其进行自然交联反应，形成硅水凝胶，即所述具有抑菌功能的硅水凝胶材料。Trimethoxy (3-methoxypropyl) silane, tetramethoxysilane, glycerol, the above antibacterial materials and water are mixed evenly according to the formula amount, and the mixture is poured into a corneal contact lens mold and left at room temperature for several hours to allow it to undergo a natural cross-linking reaction to form a silicone hydrogel, i.e., the silicone hydrogel material with antibacterial function.
实施例3Example 3
一种具有抑菌功能的硅水凝胶材料，由以下重量百分比的原料组成：三甲氧基（3-甲氧基丙基）硅烷10%、四甲氧基硅烷15%、甘油7%、抗菌材料0.5%、余量水。具体的制备步骤如下：A silicone hydrogel material with antibacterial function is composed of the following raw materials in weight percentage: 10% trimethoxy (3-methoxypropyl) silane, 15% tetramethoxy silane, 7% glycerol, 0.5% antibacterial material, and the balance water. The specific preparation steps are as follows:
S1，制备抗菌材料，其合成路线如图1所示：S1, prepare antibacterial material, the synthesis route of which is shown in Figure 1:
（1）向聚磷酸（699.3 mmol）中加入2-三氟甲基苯胺（116.6 mmol）和4,4,4-三氟乙酰乙酸乙酯（77.7 mmol）混合均匀，将混合物在180oC下搅拌6小时，通过TLC监测反应。反应结束后，在剧烈搅拌下将反应液缓慢倒入300 mL冰冷的蒸馏水中，形成沉淀。收集沉淀物并用冷蒸馏水洗涤，得到93%收率的中间体1。(1) Add 2-trifluoromethylaniline (116.6 mmol) and ethyl 4,4,4-trifluoroacetoacetate (77.7 mmol) to polyphosphoric acid (699.3 mmol) and mix well. Stir the mixture at 180° C for 6 hours and monitor the reaction by TLC. After the reaction, the reaction solution was slowly poured into 300 mL of ice-cold distilled water under vigorous stirring to form a precipitate. The precipitate was collected and washed with cold distilled water to obtain intermediate 1 with a yield of 93%.
（2）将中间体1（5 mmol）溶于100 mL干燥的DMF中，并向其中加入氯化亚砜（7.5mmol），在60℃条件下搅拌8 h；降温至室温，然后向反应液中滴加质量浓度为37 %的氨水5mL，继续反应4 h；反应结束后，将反应液进行浓缩、干燥和柱层析分离，得到中间体2。(2) Intermediate 1 (5 mmol) was dissolved in 100 mL of dry DMF, and thionyl chloride (7.5 mmol) was added thereto, and the mixture was stirred at 60 °C for 8 h. The mixture was cooled to room temperature, and 5 mL of 37% aqueous ammonia was added dropwise to the reaction mixture, and the reaction was continued for 4 h. After the reaction was completed, the reaction mixture was concentrated, dried and separated by column chromatography to obtain intermediate 2.
（3）将中间体2（10 mmol）和3-氰基苯异氰酸酯（15 mmol）加入到150 mL无水甲苯中，120℃条件下搅拌2 h，利用TLC监测反应情况。反应结束后，过滤反应液，收集沉淀并用正己烷进行洗涤，干燥后得到中间体3。(3) Intermediate 2 (10 mmol) and 3-cyanophenyl isocyanate (15 mmol) were added to 150 mL of anhydrous toluene and stirred at 120°C for 2 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was filtered, and the precipitate was collected and washed with n-hexane, and then dried to obtain intermediate 3.
（4）将中间体3（10 mmol）加至100 mL二甲基亚砜中，并向其中加入3，4二羟基苯甲醛（20 mmol），搅拌反应12 h；反应结束后，将反应液浓缩、干燥、过柱纯化得到中间体4；(4) Add intermediate 3 (10 mmol) to 100 mL of dimethyl sulfoxide, and add 3,4-dihydroxybenzaldehyde (20 mmol) thereto, and stir to react for 12 h. After the reaction, concentrate the reaction solution, dry it, and purify it by column to obtain intermediate 4.
（5）将聚赖氨酸（12 mmol，以单体计算）溶于100 mL去离子在水中，并使用NaHCO3(1M)将pH调节至8.2，向其中加入3-醛基苯硼酸（4 mmol），搅拌反应15 h；反应结束后，向反应液中加入乙醇，收集析出的沉淀并用乙醇洗涤，干燥后即可得到中间体5；(5) Dissolve polylysine (12 mmol, calculated as monomer) in 100 mL of deionized water, adjust the pH to 8.2 with NaHCO3 (1 M), add 3-formylphenylboronic acid (4 mmol), and stir for 15 h. After the reaction, add ethanol to the reaction solution, collect the precipitate, wash it with ethanol, and dry it to obtain intermediate 5.
（6）将中间体4（10 mmol）和中间体5（15 mmol，以赖氨酸单体算）加入到乙醇和水（体积比为1:1）中，搅拌反应12 h后，反应液用超纯水透析3 d（透析袋的截留分子量为2000Da），冷冻干燥后即可得到抗菌材料。(6) Intermediate 4 (10 mmol) and intermediate 5 (15 mmol, calculated as lysine monomer) were added to ethanol and water (volume ratio of 1:1). After stirring for 12 h, the reaction solution was dialyzed against ultrapure water for 3 d (the molecular weight cutoff of the dialysis bag was 2000 Da) and freeze-dried to obtain the antibacterial material.
S2，制备硅水凝胶材料：S2, preparation of silicone hydrogel material:
将三甲氧基（3-甲氧基丙基）硅烷、四甲氧基硅烷、甘油、上述抗菌材料和水按配方量混合均匀，将混合物倒入角膜接触镜模具中，在室温下放置数小时，使其进行自然交联反应，形成硅水凝胶，即所述具有抑菌功能的硅水凝胶材料。Trimethoxy (3-methoxypropyl) silane, tetramethoxysilane, glycerol, the above antibacterial materials and water are mixed evenly according to the formula amount, and the mixture is poured into a corneal contact lens mold and left at room temperature for several hours to allow it to undergo a natural cross-linking reaction to form a silicone hydrogel, i.e., the silicone hydrogel material with antibacterial function.
对比例1Comparative Example 1
一种硅水凝胶材料，由以下重量百分比的原料组成：三甲氧基（3-甲氧基丙基）硅烷10%、四甲氧基硅烷15%、甘油7%、聚赖氨酸0.5%、余量水。具体的制备步骤如下：A silicone hydrogel material is composed of the following raw materials in percentage by weight: 10% trimethoxy (3-methoxypropyl) silane, 15% tetramethoxy silane, 7% glycerol, 0.5% polylysine, and the balance water. The specific preparation steps are as follows:
将三甲氧基（3-甲氧基丙基）硅烷、四甲氧基硅烷、甘油、聚赖氨酸和水按配方量混合均匀，将混合物倒入角膜接触镜模具中，在室温下放置数小时，使其进行自然交联反应，形成硅水凝胶，即所述硅水凝胶材料。Trimethoxy (3-methoxypropyl) silane, tetramethoxy silane, glycerol, polylysine and water are uniformly mixed according to the formula amount, and the mixture is poured into a corneal contact lens mold and left at room temperature for several hours to undergo a natural cross-linking reaction to form a silicone hydrogel, i.e., the silicone hydrogel material.
上述实施例1和对比例1制备的硅水凝胶材料的SEM图如图2所示，从图2中可以看出，实施例1与对比例1的硅水凝胶材料的表明均较平整，说明本发明对聚赖氨酸改性后，不会影响硅水凝胶材料的形貌。The SEM images of the silicone hydrogel materials prepared in Example 1 and Comparative Example 1 are shown in FIG2 . As can be seen from FIG2 , the surfaces of the silicone hydrogel materials in Example 1 and Comparative Example 1 are both relatively smooth, indicating that the modification of polylysine in the present invention does not affect the morphology of the silicone hydrogel materials.
试验例1Test Example 1
为了对实施例1-3和对比例1所得硅水凝胶材料进行抗菌性能实验，选取大肠杆菌、金黄色葡萄球菌、铜绿假单胞菌和肺炎克雷伯菌四种菌种进行实验。In order to conduct antibacterial performance experiments on the silicone hydrogel materials obtained in Examples 1-3 and Comparative Example 1, four bacterial species, namely Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae, were selected for the experiments.
（1）抑菌圈(1) Inhibition zone
用PBS溶液将大肠杆菌、金黄色葡萄球菌、铜绿假单胞菌和肺炎克雷伯菌稀释至2×106CFU/mL的菌悬液，将200 μL菌悬液吸取到琼脂平板上，然后涂抹均匀，接着将实施例1-3和对比例1所得硅水凝胶材料放置在琼脂平板上，以不添加样品的菌悬液作为空白组，最后，将平板于37℃下恒温培养24 h，测定3次取平均值，每组设3个重复，结果如表1所示。Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae were diluted to a bacterial suspension of 2×106 CFU/mL with PBS solution, 200 μL of the bacterial suspension was pipetted onto an agar plate and then spread evenly. Subsequently, the silicone hydrogel materials obtained in Examples 1-3 and Comparative Example 1 were placed on the agar plate, and the bacterial suspension without adding the sample was used as a blank group. Finally, the plate was incubated at 37°C for 24 h, and the average value was taken for 3 measurements. Three replicates were set for each group. The results are shown in Table 1.
表1Table 1
从表1可以看出，实施例1-5的硅水凝胶对大肠杆菌、金黄色葡萄球菌、铜绿假单胞菌均具有较好的抑制能力，而对比例1的硅水凝胶，表现出较差的抗菌效果。It can be seen from Table 1 that the silicone hydrogels of Examples 1-5 have good inhibitory abilities against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa, while the silicone hydrogel of Comparative Example 1 exhibits poor antibacterial effects.
（2）杀菌率(2) Sterilization rate
用PBS溶液将大肠杆菌、金黄色葡萄球菌、铜绿假单胞菌和肺炎克雷伯菌稀释至108CFU/mL的菌悬液；将实施例1-3和对比例1所得硅水凝胶材料（通过正方形打孔器制备成1cm×1cm的样品）置于48孔板中灭菌2 h，然后每孔加入1 mL上述菌悬液；同时，以不添加样品的菌悬液作为空白对照组。在37℃、转速为100 rpm、相对湿度不小于90％的条件下孵育2h，取出各组硅水凝胶，置于1 mL生理盐水的孔板中，将孔板超声10 s（超声功率80 w，超声频率40 KHz），然后将生理盐水倒回至菌悬液中并将菌悬液稀释至104 CFU /mL，每组取30μL菌悬液移至已灭菌的琼脂表面，涂布均匀，再置于37℃培养24 h，最后计数琼脂培养基上的菌落数。每组重复测试3次，杀菌率结果如图3所示，图中杀菌率% =(空白对照组的菌落数-样品组的菌落数)/对照组的菌落数×100%。Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae were diluted to a bacterial suspension of 108 CFU/mL with PBS solution; the silicone hydrogel materials obtained in Examples 1-3 and Comparative Example 1 (prepared into 1 cm×1 cm samples by a square puncher) were placed in a 48-well plate for sterilization for 2 h, and then 1 mL of the above bacterial suspension was added to each well; at the same time, the bacterial suspension without adding the sample was used as a blank control group. Incubate for 2 h at 37°C, a rotation speed of 100 rpm, and a relative humidity of not less than 90%, take out each group of silicone hydrogels, place them in a well plate with 1 mL of physiological saline, ultrasonicate the well plate for 10 s (ultrasonic power 80 w, ultrasonic frequency 40 KHz), then pour the physiological saline back into the bacterial suspension and dilute the bacterial suspension to 104 CFU/mL, take 30 μL of the bacterial suspension from each group and move it to the sterilized agar surface, spread it evenly, and then culture it at 37°C for 24 h, and finally count the number of colonies on the agar medium. Each group was tested three times, and the sterilization rate results are shown in FIG3 , where sterilization rate % = (colony number of blank control group - colony number of sample group) / colony number of control group × 100%.
从图3可知，对比例1的硅水凝胶杀菌率只有75.4%，抗菌活性差。而实施例1-3的硅水凝胶杀菌率为93.4%-95.5%，说明本发明实施例1-3制备的硅水凝胶具有显著的抗菌活性。As shown in Figure 3, the bactericidal rate of the silicone hydrogel in Comparative Example 1 is only 75.4%, and the antibacterial activity is poor. However, the bactericidal rates of the silicone hydrogels in Examples 1-3 are 93.4%-95.5%, indicating that the silicone hydrogels prepared in Examples 1-3 of the present invention have significant antibacterial activity.
试验例2Test Example 2
细胞毒性Cytotoxicity
为了评估实施例1-3和对比例1所得硅水凝胶材料的细胞相容性，使用小鼠成纤维细胞L929研究各组水凝胶浸出液对细胞生长的影响。In order to evaluate the cell compatibility of the silicone hydrogel materials obtained in Examples 1-3 and Comparative Example 1, mouse fibroblasts L929 were used to study the effects of the hydrogel extracts of each group on cell growth.
选取对数期生长的成纤维细胞L929分为空白对照组、实施例1-3组和对比例1组，各组细胞加入培养基中37℃培育24 h，同时，将实施例1-3和对比例1所得硅水凝胶材料在37℃的血清培养基中浸泡24 h。然后，将各组细胞接种到96孔板中培养。一段时间后，弃培养基，除空白对照组外，其他各组添加1 mL样品浸出液培养12 h，每组3个复孔。从各组每孔中取出培养基，并添加900 μL新鲜培养基。然后，缓慢添加浓度为5 mg/mL的100 μL MTT溶液。在37℃的培养箱中继续培养4 h。将96孔板中的溶液吸出，加入1 mL二甲基亚砜（DMSO），并在黑暗中振荡20 min。使用酶标仪（1510，Thermo Fisher）测量溶液在570 nm的吸光度，各组取平均值，计算各组细胞存活率，结果参见图4。Fibroblast L929 cells growing in the logarithmic phase were selected and divided into a blank control group, Example 1-3 groups and Comparative Example 1 group. Cells in each group were added to the culture medium and cultured at 37°C for 24 h. At the same time, the silicone hydrogel materials obtained in Examples 1-3 and Comparative Example 1 were soaked in a serum culture medium at 37°C for 24 h. Then, cells in each group were inoculated into a 96-well plate for culture. After a period of time, the culture medium was discarded. Except for the blank control group, 1 mL of sample extract was added to the other groups for culture for 12 h, with 3 replicates in each group. The culture medium was removed from each well of each group, and 900 μL of fresh culture medium was added. Then, 100 μL of MTT solution at a concentration of 5 mg/mL was slowly added. Continue to culture in an incubator at 37°C for 4 h. The solution in the 96-well plate was aspirated, 1 mL of dimethyl sulfoxide (DMSO) was added, and shaken in the dark for 20 min. The absorbance of the solution at 570 nm was measured using an ELISA reader (1510, Thermo Fisher), the average value of each group was taken, and the cell survival rate of each group was calculated. The results are shown in Figure 4.
从图4可知，实施例1-3组和对比例1组所得硅水凝胶材料的细胞存活率都在95%以上，表明对成纤维细胞L929没有明显的细胞毒性。As can be seen from FIG. 4 , the cell survival rates of the silicone hydrogel materials obtained in Examples 1-3 and Comparative Example 1 were all above 95%, indicating that they had no obvious cytotoxicity to fibroblast L929.
试验例3Test Example 3
平衡含水量和接触角Balancing water content and contact angle
（1）平衡含水量(1) Balanced water content
将实施例1-3和对比例1所得硅水凝胶材料置于生理盐水中浸泡48 h，然后通过打孔器制成相同规格的正方形凝胶样品块，称取湿重Ws。然后将样品块于50℃干燥72 h，并称取干重至重量不再变化时记录水凝胶的干重Wd。每个样品测试3次，取各组平均值并计算水凝胶的平衡含水量，平衡含水量=（Ws-Wd）/Ws×100%，结果参见表2。The silicone hydrogel materials obtained in Examples 1-3 and Comparative Example 1 were soaked in physiological saline for 48 h, and then square gel sample blocks of the same specifications were made by punching, and the wet weight Ws was weighed. The sample blocks were then dried at 50° C. for 72 h, and the dry weight was weighed until the weight no longer changed, and the dry weight Wd of the hydrogel was recorded. Each sample was tested 3 times, and the average value of each group was taken and the equilibrium water content of the hydrogel was calculated. The equilibrium water content = (Ws -Wd )/Ws × 100%, and the results are shown in Table 2.
（2）接触角(2) Contact angle
使用接触角测定仪对实施例1-3和对比例1所得硅水凝胶材料的静态表面水接触角进行测量。先将各组水凝胶薄膜放置在去离子水中浸泡48 h，然后擦除水凝胶表面的水，将水凝胶沾贴在载玻片上，最后往各组样品表面上滴加5 μL水滴，待水滴稳定后，使用接触角测定仪对水滴进行拍照并测量记录图片中水滴的接触角数值。每个样品分别测量4 个不同位置的静态接触角并取平均值，结果参见表2。The static surface water contact angle of the silicone hydrogel materials obtained in Examples 1-3 and Comparative Example 1 was measured using a contact angle meter. First, each group of hydrogel films was placed in deionized water and soaked for 48 h, then the water on the surface of the hydrogel was wiped off, and the hydrogel was stuck on a glass slide. Finally, 5 μL of water droplets were added to the surface of each group of samples. After the water droplets were stable, the water droplets were photographed using a contact angle meter and the contact angle values of the water droplets in the pictures were measured and recorded. The static contact angles of 4 different positions of each sample were measured and the average value was taken. The results are shown in Table 2.
表2 各组硅水凝胶材料的平衡含水量和接触角Table 2 Equilibrium water content and contact angle of each group of silicone hydrogel materials
从表2可以看出，对比例1中硅水凝胶的平衡含水量约为38.3%，而实施例1-3硅水凝胶的平衡含水量最高为46.1%。此外，相较于对比例1的静态水接触角，实施例1-3的静态水接触角有所降低，与平衡含水量影响一致。这些结果表明通过对聚赖氨酸进行化学改性，不仅赋予了水凝胶抗菌功能，还提高了硅水凝胶的亲水性。As can be seen from Table 2, the equilibrium water content of the silicone hydrogel in Comparative Example 1 is about 38.3%, while the equilibrium water content of the silicone hydrogels in Examples 1-3 is up to 46.1%. In addition, compared with the static water contact angle of Comparative Example 1, the static water contact angles of Examples 1-3 are reduced, which is consistent with the influence of the equilibrium water content. These results show that chemical modification of polylysine not only imparts antibacterial function to the hydrogel, but also improves the hydrophilicity of the silicone hydrogel.
综上所述，本发明通过对聚赖氨酸进行化学改性，制备了结构新颖的抗菌材料，将所述抗菌材料与硅水凝胶基体进行凝胶化，制得了具有优良抗菌性能的硅水凝胶材料，该硅水凝胶材料能够有效抑制包括大肠杆菌、金黄色葡萄球菌和铜绿假单胞菌的生长。此外，本发明制备的具有抑菌功能的硅水凝胶材料还具有良好的细胞相容性和亲水性。In summary, the present invention prepares an antibacterial material with a novel structure by chemically modifying polylysine, and gelates the antibacterial material with a silicone hydrogel matrix to obtain a silicone hydrogel material with excellent antibacterial properties, which can effectively inhibit the growth of Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. In addition, the silicone hydrogel material with antibacterial function prepared by the present invention also has good cell compatibility and hydrophilicity.
以上仅为本发明的优选实施例，不限于上述的举例，对于本领域的技术人员来说，在本发明的原理下，可以有各种更改和变化。所作的任何修改、改进等，均应视为在本发明的保护范围之内。The above are only preferred embodiments of the present invention, and are not limited to the above examples. For those skilled in the art, various changes and variations are possible under the principle of the present invention. Any modifications and improvements made should be considered within the scope of protection of the present invention.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN118903471A (en)* | 2024-10-11 | 2024-11-08 | 江苏长泰药业股份有限公司 | Sodium pyruvate sustained-release nano-carrier based on pH response and preparation method and application thereof |
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| CN105189485A (en)* | 2013-03-15 | 2015-12-23 | 埃科特莱茵药品有限公司 | Novel acrylamide derivatives as antimalarial agents |
| CN107333755A (en)* | 2017-07-04 | 2017-11-10 | 南开大学 | Hydrogel preparation method with the stranded structures of G tetra- and its application in staphylococcus aureus and Escherichia coli are killed |
| CN112569402A (en)* | 2020-12-01 | 2021-03-30 | 西安交通大学 | Water-soluble silicon-based gel antibacterial wound dressing and preparation method and application thereof |
| CN113248656A (en)* | 2021-04-28 | 2021-08-13 | 暨南大学 | Multifunctional pHEMA-based corneal contact lens hydrogel material, and preparation method and application thereof |
| CN116549712A (en)* | 2023-04-23 | 2023-08-08 | 清泽医疗科技(广东)有限公司 | Degradable healing-promoting medical adhesive and preparation method thereof |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105189485A (en)* | 2013-03-15 | 2015-12-23 | 埃科特莱茵药品有限公司 | Novel acrylamide derivatives as antimalarial agents |
| CN107333755A (en)* | 2017-07-04 | 2017-11-10 | 南开大学 | Hydrogel preparation method with the stranded structures of G tetra- and its application in staphylococcus aureus and Escherichia coli are killed |
| CN112569402A (en)* | 2020-12-01 | 2021-03-30 | 西安交通大学 | Water-soluble silicon-based gel antibacterial wound dressing and preparation method and application thereof |
| CN113248656A (en)* | 2021-04-28 | 2021-08-13 | 暨南大学 | Multifunctional pHEMA-based corneal contact lens hydrogel material, and preparation method and application thereof |
| CN116549712A (en)* | 2023-04-23 | 2023-08-08 | 清泽医疗科技(广东)有限公司 | Degradable healing-promoting medical adhesive and preparation method thereof |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN118903471A (en)* | 2024-10-11 | 2024-11-08 | 江苏长泰药业股份有限公司 | Sodium pyruvate sustained-release nano-carrier based on pH response and preparation method and application thereof |
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