技术领域Technical Field
本发明属于眼科医用植入材料及器械表面修饰技术领域，具体涉及一种适可控缓释药物的超亲水涂层修饰的人工晶状体及其制备方法。The invention belongs to the technical field of surface modification of ophthalmic medical implant materials and instruments, and particularly relates to an artificial lens modified with a super-hydrophilic coating for controlled sustained-release of drugs and a preparation method thereof.
背景技术Background Art
白内障是由于人眼天然晶状体浑浊病变引起的致盲性眼科疾病，常见于中老年人群。目前，通过白内障超声乳化技术摘除病变晶状体，并联合植入人工晶状体是治疗白内障最有效的方法。然而，大量临床研究表明，人工晶状体植入后存在多种严重影响视力的并发症，其中以术后细菌性眼内炎（POE）和后囊膜混浊（PCO）最为常见。POE是由于人工晶状体表面细菌粘附和增殖形成生物膜引起，发病率在0.05-0.4%之间，是术后最严重和危险的并发症之一。眼部的血房水屏障和血视网膜屏障使得治疗眼内炎的药物难以有效作用，导致眼内炎一旦发生便具有极高的二次致盲率。临床研究报道，成人术后5年PCO发生率高达28.4%，而青少年的发生率超过90%，严重威胁患者的视力恢复。PCO是由于人工晶状体植入后，晶状体上皮细胞在后囊膜及人工晶状体表面粘附、增殖、迁移及纤维化等异物反应所致。目前，临床上主要通过激光手术进行囊膜切除治疗PCO，但二次手术可能带来晶状体脱位、角膜损伤等风险。因此，通过对人工晶状体表面进行改性，抑制细菌和细胞的粘附和增殖，成为预防POE和PCO的有效策略。Cataract is a blinding ophthalmic disease caused by the opacity of the natural lens of the human eye, which is common in the middle-aged and elderly population. At present, the most effective method for treating cataracts is to remove the diseased lens through phacoemulsification and implant an artificial lens. However, a large number of clinical studies have shown that there are many complications that seriously affect vision after artificial lens implantation, among which postoperative bacterial endophthalmitis (POE) and posterior capsule opacification (PCO) are the most common. POE is caused by the adhesion and proliferation of bacteria on the surface of the artificial lens to form a biofilm, with an incidence rate of between 0.05-0.4%, and is one of the most serious and dangerous complications after surgery. The blood-aqueous barrier and blood-retinal barrier in the eye make it difficult for drugs to effectively treat endophthalmitis, resulting in an extremely high secondary blindness rate once endophthalmitis occurs. Clinical studies have reported that the incidence of PCO in adults is as high as 28.4% 5 years after surgery, while the incidence in adolescents exceeds 90%, which seriously threatens the patient's vision recovery. PCO is caused by foreign body reactions such as adhesion, proliferation, migration and fibrosis of lens epithelial cells on the posterior capsule and the surface of the intraocular lens after intraocular lens implantation. Currently, PCO is mainly treated clinically by laser capsule removal, but secondary surgery may bring risks such as lens dislocation and corneal injury. Therefore, modifying the surface of the intraocular lens to inhibit the adhesion and proliferation of bacteria and cells has become an effective strategy to prevent POE and PCO.
近年来，在人工晶状体表面构建基于高分子聚合物网络物理掺杂负载和缓释药物的涂层，已被证明能够有效抑制细菌和细胞的粘附和增殖，显著降低了POE和PCO发生率。如中国专利CN 103071186B“一种表面改性的涂层包载药物的人工晶状体及其制备方法”，中国专利CN 115364280B“一种药物缓释型人工晶状体及其制备方法”，中国专利CN114618019B“一种可预防感染性眼内炎的人工晶状体的制备方法”，中国专利CN115708895A“一种人工晶状体材料及其制备方法和应用”。然而，带药物缓释涂层的人工晶状体虽然降低了POE和PCO的发生率，但仍存在以下瓶颈问题：（1）药物的物理负载不稳定型和缓释不精准性，药物释放周期短，难以维持长效抑制功能，并存在药物爆发性释放带来的生物安全性问题。（2）涂层缺乏防污活性，被药物杀死的细菌或晶状体细胞易堆积在涂层表面，阻碍药物的有效释放和作用。（3）涂层制备方法繁琐，载药量难控制，涂层稳定性和均一性差，导致带涂层人工晶状体的质量可控性差，难以实现商业化应用。In recent years, the construction of coatings based on the physical doping and sustained release of drugs on the surface of artificial lenses based on polymer networks has been proven to effectively inhibit the adhesion and proliferation of bacteria and cells, and significantly reduce the incidence of POE and PCO. For example, Chinese patent CN 103071186B "A surface-modified coating-loaded artificial lens and its preparation method", Chinese patent CN 115364280B "A drug-sustaining artificial lens and its preparation method", Chinese patent CN114618019B "A method for preparing an artificial lens capable of preventing infectious endophthalmitis", and Chinese patent CN115708895A "An artificial lens material and its preparation method and application". However, although artificial lenses with drug-sustaining coatings reduce the incidence of POE and PCO, they still have the following bottleneck problems: (1) The physical loading of drugs is unstable and the sustained release is imprecise, the drug release cycle is short, it is difficult to maintain long-term inhibitory function, and there are biosafety issues caused by the explosive release of drugs. (2) The coating lacks antifouling activity, and bacteria or lens cells killed by drugs tend to accumulate on the coating surface, hindering the effective release and action of the drug. (3) The coating preparation method is cumbersome, the drug loading is difficult to control, and the coating stability and uniformity are poor, resulting in poor quality controllability of coated intraocular lenses and difficulty in commercial application.
因此，如何实现涂层在人工晶状体表面的均一、稳定涂覆，同时保障涂层具有可控缓释药物功能并有效协同涂层的防污机制，是实现长效抑制POE和PCO，以及推进相关产品应用的关键技术问题。Therefore, how to achieve uniform and stable coating on the surface of the intraocular lens, while ensuring that the coating has the function of controlled sustained-release of drugs and effectively coordinates the anti-fouling mechanism of the coating, is a key technical issue for achieving long-term inhibition of POE and PCO and promoting the application of related products.
发明内容Summary of the invention
本发明的目的是为了解决上述背景技术问题，提供一种可控缓释药物的超亲水涂层修饰的人工晶状体及其制备方法。所述的涂层制备方法简易、涂层可控性良好，具备大规模应用潜力；所述的涂层通过调控负电性高分子网络与正电性药物之间的静电作用强度，从而有效保障涂层具有药物可控缓释功能；所述的涂层具有超亲水超润滑功能，可赋予涂层良好的防污性能，从而高度协同缓释药物的杀菌或抗细胞增殖功能，采用所述人工晶状体可实现术后长效抑制细菌性眼内炎和后囊膜混浊。The purpose of the present invention is to solve the above-mentioned background technical problems and provide an artificial lens modified with a super-hydrophilic coating for controlled sustained release of drugs and a preparation method thereof. The coating preparation method is simple, the coating has good controllability, and has the potential for large-scale application; the coating effectively ensures that the coating has a controlled sustained release function of drugs by regulating the electrostatic interaction strength between the negatively charged polymer network and the positively charged drug; the coating has super-hydrophilic and super-lubricating functions, which can give the coating good anti-fouling properties, thereby highly synergizing the bactericidal or anti-cell proliferation functions of the sustained release drug. The use of the artificial lens can achieve long-term inhibition of bacterial endophthalmitis and posterior capsule opacity after surgery.
针对上述背景技术问题，本发明提供的具体技术方案是：In view of the above-mentioned background technical problems, the specific technical solution provided by the present invention is:
一种可控缓释药物超亲水涂层修饰的人工晶状体，在人工晶状体表面具有可控缓释药物超亲水涂层，所述可控缓释药物超亲水涂层由底层载药部分和亲水表层部分构成，其中所述底层载药部分为由阴离子型聚氨酯树脂、带正电荷药物和多异氰酸酯类交联剂交联形成，所述亲水表层部分为由非离子型聚氨酯树脂、亲水性大分子和多异氰酸酯类交联剂交联形成。An artificial lens modified with a super-hydrophilic coating for controlled sustained drug release has a super-hydrophilic coating for controlled sustained drug release on the surface of the artificial lens, wherein the super-hydrophilic coating for controlled sustained drug release consists of a bottom drug-carrying portion and a hydrophilic surface portion, wherein the bottom drug-carrying portion is formed by cross-linking anionic polyurethane resin, positively charged drugs and a polyisocyanate cross-linking agent, and the hydrophilic surface portion is formed by cross-linking non-ionic polyurethane resin, hydrophilic macromolecules and a polyisocyanate cross-linking agent.
所述人工晶状体的制备步骤包括如下：The preparation steps of the intraocular lens include the following:
（1）用低温等离子仪对人工晶状体进行表面处理，然后在人工晶状体表面喷涂组成成分包括阴离子型聚氨酯树脂、带正电荷的药物和多异氰酸酯类交联剂的底层载药水系涂层液，高温固化，在人工晶状体表面形成底层载药部分。(1) The surface of the artificial lens is treated with a low-temperature plasma apparatus, and then a bottom drug-loaded aqueous coating liquid composed of anionic polyurethane resin, positively charged drugs and polyisocyanate cross-linking agents is sprayed on the surface of the artificial lens, and cured at high temperature to form a bottom drug-loaded portion on the surface of the artificial lens.
（2）采用含有非离子型聚氨酯树脂、亲水性大分子、多异氰酸酯类交联剂的表层水系涂层液，并通过喷涂固化的方式在经步骤（1）底层处理后的人工晶状体表面形成亲水表层部分，最终获得具有可控缓释药物的超亲水涂层修饰的人工晶状体。(2) A surface aqueous coating liquid containing a non-ionic polyurethane resin, a hydrophilic macromolecule, and a polyisocyanate crosslinking agent is used, and a hydrophilic surface layer is formed on the surface of the intraocular lens after the bottom layer treatment in step (1) by spray curing, thereby finally obtaining an intraocular lens modified with a super-hydrophilic coating having a controlled sustained release of drugs.
进一步，步骤（1）中，作为优选，等离子仪处理表面处理氧流量5-15 cm3/min、功率50-100 W、处理时间3-5 min；作为优选，所述的固化温度80-100 ℃、时间1-2 h；作为优选，所述的底层涂层厚度为5-30 μm。Furthermore, in step (1), preferably, the plasma treatment surface treatment oxygen flow rate is 5-15 cm3 /min, power is 50-100 W, and treatment time is 3-5 min; preferably, the curing temperature is 80-100 °C, and the time is 1-2 h; preferably, the bottom coating thickness is 5-30 μm.
进一步，步骤（1）中，底层载药水系涂层液的阴离子型聚氨酯树脂为羧基型阴离子聚氨酯树脂或磺酸基型阴离子聚氨酯树脂中的一种或多种；作为优选所述的阴离型聚氨酯树脂分子量为5-20 kDa，酸值为10-30mg/g。Furthermore, in step (1), the anionic polyurethane resin of the bottom drug-loaded aqueous coating liquid is one or more of a carboxyl-type anionic polyurethane resin or a sulfonic acid-type anionic polyurethane resin; preferably, the anionic release polyurethane resin has a molecular weight of 5-20 kDa and an acid value of 10-30 mg/g.
进一步，步骤（1）中底层载药部分的水系涂层液所述的带正电荷的药物为抗增殖药物或抗生素，其中抗增殖药物为阿霉素、表阿霉素、吡柔比星、吉西他滨中的一种或多种，作为优选药物使用浓度为50-100 mg/mL；抗生素为万古霉素、阿米卡星、庆大霉素中的一种或多种，作为优选药物使用浓度为50-100 mg/mL。Furthermore, the positively charged drug in the aqueous coating liquid of the bottom drug-carrying part in step (1) is an antiproliferative drug or an antibiotic, wherein the antiproliferative drug is one or more of doxorubicin, epirubicin, pirarubicin, and gemcitabine, and the preferred drug concentration is 50-100 mg/mL; the antibiotic is one or more of vancomycin, amikacin, and gentamicin, and the preferred drug concentration is 50-100 mg/mL.
进一步，步骤（2）所述涂层的亲水表层部分，表层水系涂层液中非离子型聚氨酯树脂分子量为2-10 kDa，作为优选使用浓度为5-15 wt%。Furthermore, in the hydrophilic surface layer of the coating in step (2), the molecular weight of the non-ionic polyurethane resin in the surface aqueous coating liquid is 2-10 kDa, and the preferred concentration is 5-15 wt%.
进一步，步骤（2）所述涂层的亲水表层部分的亲水性大分子为聚乙烯吡咯烷酮、聚丙烯酰胺、聚乙二醇、聚乙烯醇中的一种或多种；作为优选所述的亲水性大分子分子量为70-100 kDa。Furthermore, the hydrophilic macromolecules of the hydrophilic surface layer of the coating in step (2) are one or more of polyvinyl pyrrolidone, polyacrylamide, polyethylene glycol, and polyvinyl alcohol; preferably, the hydrophilic macromolecules have a molecular weight of 70-100 kDa.
采用以上技术方案所制得的带涂层人工晶状体，进一步，其带涂层表面水接触角为0-5°，表面动态摩擦力为0.01-0.05N。The coated intraocular lens prepared by the above technical solution further has a coated surface water contact angle of 0-5° and a surface dynamic friction force of 0.01-0.05N.
本发明所提供的一种可控缓释药物的超亲水涂层，如上所述，由底层载药部分和亲水表层部分构成，其中所述底层载药部分为由阴离子型聚氨酯树脂、带正电荷药物和多异氰酸酯类交联剂交联形成，可通过喷涂底层载药水系涂层液制得，所述亲水表层部分为由非离子型聚氨酯树脂、亲水性大分子和多异氰酸酯类交联剂交联形成，可通过喷涂固化表层水系涂层液制得。该涂层可不仅仅用于人工晶状体，也可用于有类似缓释药物及长效抗污功能需求的其他医用植入器械表面。The present invention provides a super-hydrophilic coating for controlled sustained drug release, as described above, which is composed of a bottom drug-carrying part and a hydrophilic surface part, wherein the bottom drug-carrying part is formed by cross-linking anionic polyurethane resin, positively charged drugs and polyisocyanate cross-linking agents, and can be prepared by spraying a bottom drug-carrying aqueous coating liquid, and the hydrophilic surface part is formed by cross-linking non-ionic polyurethane resin, hydrophilic macromolecules and polyisocyanate cross-linking agents, and can be prepared by spraying and curing the surface aqueous coating liquid. The coating can be used not only for artificial lenses, but also for the surfaces of other medical implants with similar sustained drug release and long-term anti-fouling functions.
基于上述技术方案，本发明的有益效果主要体现在制备技术和应用功能两方面，具体如下：Based on the above technical solution, the beneficial effects of the present invention are mainly reflected in two aspects: preparation technology and application function, as follows:
（1）涂层的制备技术：通过易于规模化生产的喷涂热固化方式实现涂层实用化制备技术，并基于聚氨酯树脂的优良成膜性以及多异氰酸酯基交联剂的界面化学交联作用，实现涂层的均一稳定构建，使涂层更具商业化应用潜力；(1) Coating preparation technology: The coating preparation technology is realized through the spray thermal curing method that is easy to scale up. Based on the excellent film-forming property of polyurethane resin and the interfacial chemical cross-linking effect of polyisocyanate-based cross-linking agent, the uniform and stable construction of the coating is achieved, making the coating more commercially applicable.
（2）涂层的可控药物缓释功能：通过改变聚氨酯树脂的负电性强度，可有效调控其与正电性药物之间的静电作用强度，从而实现涂层对药物释放量和缓释时长的精准可控功能，保障药物缓释过程中的安全性和长效性。(2) Controllable drug release function of the coating: By changing the negative charge strength of the polyurethane resin, the electrostatic interaction strength between it and the positively charged drug can be effectively regulated, thereby achieving the coating's precise controllable function of drug release amount and sustained release duration, ensuring the safety and long-term effectiveness of the drug during sustained release.
（3）涂层的协同作用功能：具有超亲水超润滑功能的防污表层，不仅可有效阻抗蛋白质、活细菌和细胞在人工晶状体表面的粘附，还能有效避免被药物杀死的细菌和细胞在人工晶状体表面的累积，基于底层可控缓释药物功能和表层防污机制之间的有效协同，实现对细菌性眼内炎和后囊膜混浊的高效抑制。(3) Synergistic function of the coating: The anti-fouling surface layer with super-hydrophilic and super-lubricating functions can not only effectively resist the adhesion of proteins, living bacteria and cells on the surface of the intraocular lens, but also effectively prevent the accumulation of bacteria and cells killed by drugs on the surface of the intraocular lens. Based on the effective synergy between the controlled sustained-release drug function of the bottom layer and the anti-fouling mechanism of the surface layer, it can achieve efficient inhibition of bacterial endophthalmitis and posterior capsule opacity.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1是不同涂层修饰的人工晶状体的药物释放累计百分比。Figure 1 shows the cumulative percentage of drug release from intraocular lenses modified with different coatings.
图2是不同涂层修饰的人工晶体和无涂层人工晶状体表面蛋白质吸附量。Figure 2 shows the amount of protein adsorption on the surface of intraocular lenses modified with different coatings and uncoated intraocular lenses.
图3是不同涂层修饰的人工晶体和无涂层人工晶状体循环10次测试的杀菌率。Figure 3 shows the sterilization rates of intraocular lenses modified with different coatings and uncoated intraocular lenses after 10 cycles of testing.
具体实施方式DETAILED DESCRIPTION
以下实施例旨在更清晰地阐明本发明的目的、技术方案以及优点。需要指出的是，这些实施例仅用于解释和说明本发明，并不对其进行限定。本领域的技术人员根据本文所述内容进行的非本质改进和调整仍属于本发明的保护范围。The following examples are intended to more clearly illustrate the purpose, technical solutions and advantages of the present invention. It should be noted that these examples are only used to explain and illustrate the present invention and are not intended to limit it. Non-essential improvements and adjustments made by those skilled in the art based on the contents described herein still fall within the scope of protection of the present invention.
实施例1Example 1
阴离子聚氨酯树脂的合成：Synthesis of anionic polyurethane resin:
在一个带有氮气进出口、干燥管、机械搅拌器、温度计和水冷冷凝器的500 mL四颈圆底烧瓶中进行以下实验。首先，按照参照表1中的化学计量比，取相应量的聚己内酯二元醇和异佛尔酮二异氰酸酯，并向反应器中滴加0.05 wt%的有机锡催化剂，在85 ℃下反应4小时。随后，加入化学计量比的阴离子型扩链剂，其中，羧基型阴离子聚氨酯树脂加入2,2-二羟甲基丁酸，磺酸基型阴离子聚氨酯树脂加入2-[(2-氨基乙基)氨基]乙磺酸钠盐，在85℃下反应4小时。在反应过程中，逐渐滴加少量丙酮以降低体系黏度。再次加入化学计量比的乙二胺，在85 ℃下继续反应4小时。最后，加入三乙胺和300 mL去离子水，并在1000 r/min的搅拌条件下进行乳化分散，得到固含量为30%的羧基型阴离子聚氨酯树脂。其中PU-0为不含有阴离子组份的聚氨酯树脂作为对比例1。The following experiment was carried out in a 500 mL four-necked round-bottom flask equipped with a nitrogen inlet and outlet, a drying tube, a mechanical stirrer, a thermometer, and a water-cooled condenser. First, according to the stoichiometric ratio in Table 1, the corresponding amount of polycaprolactone diol and isophorone diisocyanate were taken, and 0.05 wt% of an organic tin catalyst was added to the reactor and reacted at 85 °C for 4 hours. Subsequently, a stoichiometric ratio of anionic chain extender was added, wherein 2,2-dihydroxymethylbutyric acid was added to the carboxyl anionic polyurethane resin, and 2-[(2-aminoethyl)amino]ethanesulfonic acid sodium salt was added to the sulfonic acid anionic polyurethane resin, and the reaction was carried out at 85 °C for 4 hours. During the reaction, a small amount of acetone was gradually added to reduce the viscosity of the system. A stoichiometric ratio of ethylenediamine was added again, and the reaction was continued at 85 °C for 4 hours. Finally, triethylamine and 300 mL of deionized water were added, and emulsified and dispersed under stirring conditions of 1000 r/min to obtain a carboxyl anionic polyurethane resin with a solid content of 30%. Among them, PU-0 is a polyurethane resin without anionic components as comparative example 1.
表1 不同阴离子聚氨酯合成摩尔投料比和酸值Table 1 Molar feed ratio and acid value of different anionic polyurethane synthesis
阴离子聚氨酯树脂表征：Anionic polyurethane resin characterization:
使用全自动电位滴定仪对其溶解在乙醇-甲苯混合溶液中的酸值进行测定，结果以mg KOH/g为单位表示。测试结果如表1所示，结果表明通过调控阴离子型扩链剂使用量，可获得不同阴离子含量的聚氨酯树脂。The acid value of the polyurethane resin dissolved in an ethanol-toluene mixed solution was measured using a fully automatic potentiometric titrator, and the result was expressed in mg KOH/g. The test results are shown in Table 1, which show that polyurethane resins with different anion contents can be obtained by adjusting the amount of anionic chain extender used.
实施例2Example 2
底层载药部分的具体制备步骤如下：The specific preparation steps of the bottom drug-carrying part are as follows:
（1）采用等离子仪，在氧流量为10 cm3/min和功率为50W的条件下对聚丙烯酸酯类人工晶状体处理3min后待用。(1) Polyacrylate intraocular lenses were treated with a plasma apparatus at an oxygen flow rate of 10 cm3 /min and a power of 50 W for 3 minutes and then set aside for use.
（2）配置含有实施例1中合成的阴离子型聚氨酯树脂、带正电荷的药物、多异氰酸酯类交联剂的水系涂层液。为了证明通过改变聚氨酯树脂的负电性强度，可有效调节其与正电性药物之间的静电作用强度，实现药物缓释量和缓释时长的精准调控。水系涂层液配置使用量具体如表2所示。表2中涂层样品分别采用表1中相对应的聚氨酯样品，其中PU-0为实施例1中即不带阴离子组份的聚氨酯树脂制备的载药涂层，药物选用为等量的阿霉素和阿米卡星。(2) Prepare an aqueous coating liquid containing the anionic polyurethane resin synthesized in Example 1, a positively charged drug, and a polyisocyanate crosslinking agent. In order to prove that by changing the negative charge strength of the polyurethane resin, the electrostatic interaction strength between it and the positively charged drug can be effectively adjusted to achieve precise control of the drug sustained release amount and sustained release duration. The specific amount of aqueous coating liquid used is shown in Table 2. The coating samples in Table 2 respectively use the corresponding polyurethane samples in Table 1, where PU-0 is the drug-loaded coating prepared from the polyurethane resin without anionic components in Example 1, and the drugs selected are equal amounts of doxorubicin and amikacin.
表2 载药底层水系涂层液成分含量Table 2 Content of drug-carrying bottom aqueous coating liquid
（3）在处理后的人工晶状体表面喷涂步骤（2）中制备的水系涂层液，于90 ℃下固化2 h，获得载药底层修饰的人工晶状体。(3) Spraying the aqueous coating liquid prepared in step (2) on the treated surface of the intraocular lens, and curing at 90° C. for 2 h to obtain an intraocular lens modified with a drug-loaded bottom layer.
底层载药部分的表征：Characterization of the bottom drug loading part:
（1）药物释放量测试：将实施例2制备的不同载药底层修饰的人工晶状体浸泡在PBS缓冲液中（10 mL，pH7.4），于37 ℃下孵育。在第1、3、5、7、10、30、60、120、180、210、240、360天，从释放介质中提取500 µL的释药液，并重新加入500 µL pH为7.4新鲜PBS溶液。然后，通过紫外分光光度法测量药物释放液吸光度值，并根据标准药物释放曲线计算药物释放量。累计药物释放量如图1所示。可以看出，采用不含阴离子组分的聚氨酯树脂制得的载药底层出现了前期爆发性释放，且释放周期仅为120天。相反，利用阴离子型聚氨酯树脂制备的载药底层均展示出平稳且长效的药物释放特性。同时，阴离子型聚氨酯树脂中的阴离子含量可有效调控带正电荷药物的缓释量和缓释时长。(1) Drug release test: The intraocular lenses modified with different drug-loaded bottom layers prepared in Example 2 were immersed in PBS buffer (10 mL, pH 7.4) and incubated at 37 °C. On the 1st, 3rd, 5th, 7th, 10th, 30th, 60th, 120th, 180th, 210th, 240th, and 360th days, 500 μL of drug release solution was extracted from the release medium, and 500 μL of fresh PBS solution with a pH of 7.4 was added again. Then, the absorbance of the drug release solution was measured by UV spectrophotometry, and the drug release amount was calculated according to the standard drug release curve. The cumulative drug release amount is shown in Figure 1. It can be seen that the drug-loaded bottom layer prepared by polyurethane resin without anionic components showed an early burst release, and the release period was only 120 days. In contrast, the drug-loaded bottom layers prepared by anionic polyurethane resins all showed stable and long-lasting drug release characteristics. At the same time, the anion content in the anionic polyurethane resin can effectively regulate the sustained release amount and sustained release duration of positively charged drugs.
实施例3Example 3
表层亲水润滑组份的具体制备步骤如下：The specific preparation steps of the surface hydrophilic lubricating component are as follows:
（1）采用非离子型聚氨酯树脂、亲水性大分子、多异氰酸酯类交联剂制得表层水系涂层液，三者配比依次为 15 wt%，5 wt%，0.5 wt%。其中亲水性大分子为分子量为90 kDa聚乙烯吡咯烷酮（PVP）、100 kDa聚丙烯酰胺（PAM）、60 kDa的聚乙二醇（PEG）、20 kDa聚乙烯醇（PVA）中的一种。(1) A surface water-based coating liquid was prepared using a nonionic polyurethane resin, a hydrophilic macromolecule, and a polyisocyanate crosslinking agent, with the ratio of the three being 15 wt%, 5 wt%, and 0.5 wt%, respectively. The hydrophilic macromolecule was one of the following: 90 kDa polyvinyl pyrrolidone (PVP), 100 kDa polyacrylamide (PAM), 60 kDa polyethylene glycol (PEG), and 20 kDa polyvinyl alcohol (PVA).
（2）通过喷涂的方式在经载药底层处理后的人工晶状体表面（即实施例2中PU-S2样品）形成亲水表层，在90 ℃下固化3 h，最终获得具有可控缓释药物的超亲水涂层修饰的人工晶状体。制备得到的涂层分别记为PU-S2/PVP、PU-S2/PAM、PU-S2/PEG、PU-S2/PVA。(2) A hydrophilic surface layer was formed on the surface of the intraocular lens treated with the drug-loaded base layer (i.e., the PU-S2 sample in Example 2) by spraying, and then cured at 90 °C for 3 h to finally obtain an intraocular lens modified with a super-hydrophilic coating having controlled sustained drug release. The prepared coatings were recorded as PU-S2/PVP, PU-S2/PAM, PU-S2/PEG, and PU-S2/PVA, respectively.
测试例1Test Example 1
涂层的亲水润滑性能测试：使用OCA20型接触角测量仪对不同亲水大分子表层修饰的人工晶状体的水接触角进行测试。在测试中，使用经过煮沸并冷却的去离子水作为测试液体，测试体积为5 μL。结果如表3所示，对比不带涂层人工晶状体表面的水接触角为75.5°，四种亲水性大分子修饰的人工晶状体表面的接触角均低于5°，表明这些涂层均具有超亲水性能。Test of hydrophilic lubricity of coating: The water contact angle of intraocular lenses modified with different hydrophilic macromolecules was tested using an OCA20 contact angle meter. In the test, deionized water that had been boiled and cooled was used as the test liquid, and the test volume was 5 μL. The results are shown in Table 3. Compared with the water contact angle of the uncoated intraocular lens surface of 75.5°, the contact angles of the intraocular lens surfaces modified with four hydrophilic macromolecules were all lower than 5°, indicating that these coatings all have superhydrophilic properties.
使用动态摩擦系数仪测试了带涂层和不带涂层的人工晶状体的表面动态摩擦力。样品在去离子水中浸泡30 s后，以100 mm/min的速率进行测试。测试结果如表3所示，四种亲水性大分子修饰的人工晶状体表面的动态摩擦力均在0.01-0.05N之间，证明这些涂层均具有超润滑特性。The dynamic friction force of the surface of the coated and uncoated intraocular lenses was tested using a dynamic friction coefficient meter. After the samples were immersed in deionized water for 30 s, they were tested at a rate of 100 mm/min. The test results are shown in Table 3. The dynamic friction force of the surface of the four hydrophilic macromolecule-modified intraocular lenses was between 0.01 and 0.05 N, proving that these coatings all have superlubricity.
表3. 无涂层人工晶状体和四种涂层修饰的人工晶状体表面水接触角和动态摩擦力Table 3. Water contact angle and dynamic friction of uncoated intraocular lenses and intraocular lenses modified with four coatings
测试例2：Test Example 2:
涂层的防污性能评价：将浓度为2 mg/L的2 mL牛血清白蛋白溶液与不同处理的人工晶状体共培养24 h，包括无涂层人工晶状体和四种不同亲水大分子表层修饰的人工晶状体。培养结束后，取出样品并进行三次充分的PBS洗涤。随后，将洗涤后的样品加入含有1wt%十二烷基硫酸钠的PBS溶液（200 μL）中，并在超声功率为100W的条件下处理。最后，利用紫外-可见分光光度计在562 nm处记录溶液的吸光度，并根据标准曲线计算蛋白质含量。测试结果如图2所示，经亲水性大分子表层修饰的人工晶状体表面的蛋白质吸附量显著低于无涂层的人工晶状体。这表明这些涂层显著提高了人工晶状体的防污性能。Evaluation of the antifouling performance of the coating: 2 mL of bovine serum albumin solution with a concentration of 2 mg/L was co-cultured with different treated intraocular lenses for 24 h, including uncoated intraocular lenses and intraocular lenses modified with four different hydrophilic macromolecules. After the incubation, the samples were removed and washed three times with PBS. Subsequently, the washed samples were added to a PBS solution (200 μL) containing 1wt% sodium dodecyl sulfate and treated with an ultrasonic power of 100 W. Finally, the absorbance of the solution was recorded at 562 nm using a UV-visible spectrophotometer, and the protein content was calculated based on the standard curve. The test results are shown in Figure 2. The amount of protein adsorption on the surface of the intraocular lens modified with a hydrophilic macromolecule surface was significantly lower than that of the intraocular lens without a coating. This indicates that these coatings significantly improve the antifouling performance of the intraocular lens.
测试例3：Test Example 3:
长效杀菌性能评价：采用表皮葡萄球菌作为致病菌模型，按照抗菌标准ISO22196:2011评估了四种亲水涂层人工晶状体连续10次的抗菌性能。对照样品为不带涂层的人工晶状体和载药底层修饰的人工晶状体。测试结果如图3，与不具有任何杀菌性能的空白人工晶状体相比，载药底层修饰的人工晶状体表现出优异的杀菌性能。然而，在5次循环后，其杀菌率从初始的99.9%降低至85.5%。与之相反，四种亲水涂层人工晶状体在循环测试中接触杀菌效率持续保持在99.9%以上。这一结果证明了底层/表层的协同防污和杀菌作用机制，可赋予涂层在应用过程中的长效抗菌活性，从而长效预防人工晶状体植入后潜在的细菌性眼内炎。Evaluation of long-term bactericidal performance: Staphylococcus epidermidis was used as a pathogenic bacteria model, and the antibacterial performance of four hydrophilic coated intraocular lenses was evaluated for 10 consecutive times according to the antibacterial standard ISO22196:2011. The control samples were uncoated intraocular lenses and intraocular lenses modified with drug-loaded bottom layers. The test results are shown in Figure 3. Compared with blank intraocular lenses without any bactericidal properties, the intraocular lenses modified with drug-loaded bottom layers showed excellent bactericidal performance. However, after 5 cycles, its bactericidal rate decreased from the initial 99.9% to 85.5%. In contrast, the contact bactericidal efficiency of the four hydrophilic coated intraocular lenses continued to remain above 99.9% in the cyclic test. This result proves the synergistic antifouling and bactericidal mechanism of the bottom layer/top layer, which can give the coating a long-term antibacterial activity during the application process, thereby preventing potential bacterial endophthalmitis after intraocular lens implantation.
测试例4：Test Example 4:
将人工晶状体样品与晶状体上皮细胞在24孔板中共孵育，每孔接种105个细胞。细胞在37°C、5% CO2条件下培养，分别在1天、10天和30天取样，每日更换培养液。实验样品包括空白人工晶状体、PU-S2涂层修饰的人工晶状体和PU-S2/PVP涂层修饰的人工晶状体。在预设时间点，将人工晶状体取出并用PBS冲洗，再经4%戊二醛固定和梯度酒精脱水处理，随后通过扫描电子显微镜观察样品表面，统计表面粘附细胞数量。同时，通过CCK-8法测量细胞上清液中的细胞活性。细胞数量如表4所示，对比空白人工晶状体和PU-S2涂层修饰的人工晶状体，基于PU-S2/PVP涂层修饰的人工晶状体可控缓释药物功能和防污机制的协同作用，该样品可更为高效且长效地抑制晶状体上皮细胞增殖和迁移，从而降低人工晶状体植入后的后囊膜混浊发病率。此外，细胞活性评价结果如表5所示，相比于PU-S2涂层初期药物爆发性释放所带来的高细胞毒性问题，PU-S2/PVP涂层的可控缓释药物特性表现出低细胞毒性，确保了其在应用过程中的生物安全性。The intraocular lens samples were co-incubated with lens epithelial cells in a 24-well plate, with 105 cells seeded per well. The cells were cultured at 37°C and 5% CO2 , and samples were taken at 1 day, 10 days, and 30 days, respectively, and the culture medium was changed daily. The experimental samples included blank intraocular lenses, intraocular lenses modified with PU-S2 coatings, and intraocular lenses modified with PU-S2/PVP coatings. At the preset time point, the intraocular lenses were removed and rinsed with PBS, fixed with 4% glutaraldehyde, and dehydrated with gradient alcohol. The sample surface was then observed by scanning electron microscopy, and the number of cells adhered to the surface was counted. At the same time, the cell activity in the cell supernatant was measured by CCK-8 method. The number of cells is shown in Table 4. Compared with the blank intraocular lens and the intraocular lens modified with PU-S2 coating, based on the synergistic effect of the controlled sustained-release drug function and anti-fouling mechanism of the intraocular lens modified with PU-S2/PVP coating, the sample can more efficiently and long-term inhibit the proliferation and migration of lens epithelial cells, thereby reducing the incidence of posterior capsule opacity after intraocular lens implantation. In addition, the results of cell activity evaluation are shown in Table 5. Compared with the high cytotoxicity problem caused by the initial explosive release of drugs in the PU-S2 coating, the controlled sustained-release drug characteristics of the PU-S2/PVP coating show low cytotoxicity, ensuring its biological safety during application.
表4 不同样品表面粘附细胞平均数量Table 4 Average number of cells adherent to the surface of different samples
表5 不同样品的细胞毒性测试结果Table 5 Cytotoxicity test results of different samples
测试例5：Test Example 5:
涂层稳定性评价：将PU-S2/PVP涂层修饰的人工晶状体置于生理盐水中静态浸泡180天后，按照测试例1和测试例2的方法分别测试涂层的亲水性、表面摩擦系数和蛋白质粘附量。结果显示，经过180天的静态浸泡，涂层的表面水接触角为5.7 ± 2.2°，动态摩擦力为0.03 ± 0.007 N，蛋白质粘附量为1.8 ± 0.19 μg/cm²，与浸泡前相比无显著变化，证明涂层具有良好的稳定性。Evaluation of coating stability: After the PU-S2/PVP coating-modified intraocular lens was statically immersed in saline for 180 days, the hydrophilicity, surface friction coefficient and protein adhesion of the coating were tested according to the methods of Test Example 1 and Test Example 2. The results showed that after 180 days of static immersion, the surface water contact angle of the coating was 5.7 ± 2.2°, the dynamic friction force was 0.03 ± 0.007 N, and the protein adhesion was 1.8 ± 0.19 μg/cm², which showed no significant changes compared with before immersion, proving that the coating has good stability.
以上所述仅为本发明的部分较佳实施例，仅用于帮助理解本发明，并不用以限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变化和改进。这些都属于本发明的保护范围。The above description is only part of the preferred embodiments of the present invention, which is only used to help understand the present invention and is not intended to limit the present invention. It should be pointed out that for those skilled in the art, several changes and improvements can be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.
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