抗黏附与感染响应释放型抗菌涂层的构建及其在导尿管中的应用研究

Construction of antibacterial coatings is one of the promising strategies for inhibition of medical device-related infections. Conventional coating materials with single functionality are not able to kill bacteria or they are vulnerable to bio-fouling. Hence, they have limited efficacy in the long-term clinical applications. Currently, it is highly desirable to develop antibacterial coating materials with multi-functionality and infection-responsive capability to actively inhibit bacterial infections and its related complications. This proposal aims to develop an intelligent antibacterial coating based on multi-layer structure. The coating integrates antifouling mechanism and infection-responsive release-killing mechanism to achieve high and prolonged antibacterial efficacy, and it releases antimicrobial agents through infection-responsive mechanism to inhibit the related complications. Copper ions will be used to crosslink alginate, and complex with tannic acid to form a coating on urinary catheter. Copper ions serve as the antimicrobial agent, and tannic acids serve as the urease inhibitor to construct the inner antimicrobial “reservoir” layer. In the meantime, antifouling hydrophilic polymer will be grafted as the outer layer of the coating. In this manner, a multi-functional coating integrating antifouling property and infection-responsive release-killing property will be prepared. This proposal will focus on studying: (i) the effect of copper content, copper valence state, coating structure on the infection-responsive release-killing properties of the coating; (ii) possible synergistic effect between the antifouling mechanism and release-killing mechanism; and (iii) in vivo antibacterial and anti-encrustation performance of the coating on urinary catheter in animal model. The results from this proposal will facilitate the design and construction of coatings integrating multiple antibacterial mechanisms and infection-responsive property, and hence, it will provide a new strategy for combating medical device-related infections.

构建抗菌涂层材料是抑制医疗器械相关感染的重要手段。传统的涂层材料抗菌效能单一，无法杀死细菌或易被生物污损，长期临床效果欠佳。发展多功能、响应型抗菌涂层材料，主动抑制细菌感染及其并发症，是重要发展趋势。本项目拟发展一种基于多层结构、兼备抗黏附和响应型释放机制的智能抗菌涂层，以实现高效持久抗菌，并通过响应性地释放杀菌剂，抑制并发症。将以导尿管为模型，采用铜离子交联海藻酸制备涂层，复合单宁酸，利用铜离子的抑菌性，及单宁酸对尿素酶的抑制功能，构筑响应型抗菌剂“仓库”内层；同时，在外层修饰抗生物污损的亲水高分子，制备既抗黏附又能响应释放杀菌剂的多功能涂层。将着重研究抗菌剂的含量、价态、涂层结构等对响应释放杀菌性能的影响；研究表面抗生物污损与释放杀菌机制协同作用的规律；将其应用于导尿管，通过动物实验评估其体内抑菌性能。本项目将通过构建抗黏附与响应释放杀菌协同的涂层，为对抗医疗器械相关感染提供新的策略。

构筑安全高效、可根据环境变化响应释放抗菌剂的抗菌涂层材料是抑制植介入器械感染的一个重要手段。本项目在表面涂层引入金属离子、天然多酚、医用抗菌剂等，利用金属配位作用、氢键、静电作用、疏水缔合等一系列非共价作用，将抗菌剂与涂层形成可逆交联结构，引入pH响应、力致响应等智能响应机制，构筑多机制协同的智能抗菌涂层。以导尿管相关尿路感染为模型，研究上述涂层的智能响应机制，抗菌抗尿结石形成性能，体外细胞毒性及动物体内安全性有效性。本项目的研究表明，单宁酸-铜离子复合涂层、单宁酸-聚两性离子涂层可通过环境pH变化调控金属离子与单宁酸的释放行为，对于常见尿路感染细菌具有良好的抑制能力。单宁酸-聚两性离子涂层可作为负载临床常用抗菌剂的 “仓库”，进一步提升表面抗菌能力。利用胶束负载抗菌剂并复合至水凝胶网络中作为交联单元，可实现水凝胶的力致响应释放抗菌剂，结合表面抗污功能，实现抗生物污损与释放杀菌协同作用的效果。上述抗菌涂层均具有良好的生物相容，其中单宁酸-铜离子涂层修饰的导尿管在新西兰兔体内留置试验中表现出良好的抗菌与抗尿结石形成能力和生物安全性。本项目的开展为设计构建新型安全有效的多机制协同作用的抗菌涂层，提供了新的思路与方法，具有良好的应用前景。