Development of a novel paradigm for local antimicrobial chemotherapy: bacterial protease activated antimicrobial release from hydrogel device coatings

在英国，医疗保健的改善和人口的稳步增长导致了男性和女性平均预期寿命的增加和英国人口的稳步老龄化。人口的增加，特别是老年人或老龄化人口的增加，将对国民保健制度产生重大影响。人口老龄化需要更多的医疗、住院和手术/矫正程序。在这方面，插入患者体内（以帮助或支持其正常功能）的医疗装置（例如导管）的使用现在在各种临床环境中常规且频繁地使用。尽管使用插入式医疗器械具有实质性益处，但已报告潜在严重并发症的发生率高得令人担忧。一般而言，与插入的医疗器械相关的并发症导致患者住院时间增加、再次入院，在非常严重的情况下，导致患者死亡增加。在使用这些设备时出现的最常见的问题之一是与设备相关的感染，其中细菌或真菌在设备表面上生长并形成称为生物膜的“受保护的社区”。一旦在装置上形成生物膜，就极难在不移除装置的情况下治疗感染。根据医疗器械的部位，这可能是一个简单的过程（泌尿道），如果不舒服和不方便，或者可能需要严重和危及生命的手术（即静脉导管或心脏假体）。使用插入式医疗器械的这一方面是最严重和关键的缺点，否则是一种高效，有益和通常简单的医疗治疗。显然，迫切需要通过开发新的和创新的医疗器械来改善现状，这些医疗器械能够主动抵抗和预防感染，从而降低医疗器械相关感染的发生率。该研究提案的主要目标是通过开发新的创新材料来提高需要此类医疗器械的患者的有效性和生活质量，这些材料通过释放抗生素来应对感染微生物的存在。在感染过程中，细菌使用非常特异的酶来分解周围组织的蛋白质和其他分子。该项目旨在利用这些非常特异的蛋白质切割酶（称为蛋白酶）来激活新型器械涂层中的抗生素释放。通过这种方式，抗生素分子仅在器械相关感染发展期间存在感染细菌时释放。抗生素将以杀死感染细菌所需的浓度积聚在器械表面，从而保护器械并最终保护患者免受相关感染。因此，抗生素释放与感染微生物的存在相协调，使得装置不会永久释放药物/难以长期维持的情况以及已显示导致耐药性细菌（例如MRSA）出现的特征。该项目的主要结局是通过改善这些器械的抗菌活性和寿命，改善依赖插入医疗器械使用治疗的患者的极不满意状况。该项目还将通过减少住院时间和再入院率来降低与这种医疗有关的费用，从而为NHS带来明显的好处。这将最终为许多其他医疗保健倡议和方案腾出资金，从而改善国民保健制度向病人提供的整体服务。此外，这些创新技术的发展通过产生增值产品为医疗器械行业带来了好处，使英国能够在世界市场上有效竞争。

In the UK improved healthcare and a steadily growing population has resulted in an increase in the average male and female life expectancy and a steadily aging UK population. An increase in the population, but especially the elderly or aging population, is set to have major consequences for the NHS. The aging population requires a greater number of medical treatments, hospital admissions and surgical/corrective procedures. In this respect, the use of medical devices (such as catheters) which are inserted into the patients body (to aid or support it's normal functions) are now routinely and frequently used in a variety of clinical settings. Although the use of inserted medical devices has substantial benefits, a worryingly high incidence of potentially serious complications has been reported. In general, complications associated with inserted medical devices lead to an increase in the time spent by patients in hospital, readmissions to hospital and in very serious cases, increase in patient deaths. One of the most common problems arising in the use these devices is the infection associated with the device, where bacteria or fungi grow on the device surface and form a 'protected community' called a biofilm. Once biofilms form on the device it is extremely difficult to treating the infection, once established, without having to remove the device. Depending on the site of the medical device this can be either a simple (urinary tract), if uncomfortable and inconvenient, process or may require serious and life-threatening surgery (i.e. venous catheters or heart prostheses). This aspect of the use of inserted medical devices is the most serious and critical disadvantage to what is otherwise a highly effective, beneficial and often simple medical treatment. Clearly, there is an urgent need to improve the current situation by the development of new and innovative medical devices which actively resist and prevent infection, thereby reducing the incidence of medical device-related infection. The main objective of this research proposal is to improve effectiveness and quality of life for patients who require such medical devices via the development of new, innovative materials which respond to the presence of infecting microorganisms by the release of antibiotic agents. During infection, bacteria use very specific enzymes to break down surrounding tissue proteins and other molecules. This project is aims to harness these very specific protein cutting enzymes, known as proteases, to activate antibiotic release from novel device coatings. In this way antibiotic molecules are released only when the infecting bacteria are present during the development of device-related infection. Antibiotics will accumulate at the device surface at concentrations necessary to kill the infecting bacteria, thus protecting the device, and ultimately the patient, from associated infections. Antibiotic release is thus coordinated with the presence of the infecting microorganisms, such that the device is not permanently releasing drug / a situation difficult to maintain in the long-term and a feature that has been shown to lead to emergence of resistant bacteria such as MRSA. The primary outcome of this project is to improve the highly unsatisfactory situation for patients whose therapy relies on inserted medical device usage by improving the antimicrobial activity and lifetime of these devices. The project will also furnish clear benefits to the NHS by reducing the costs associated with this medical treatment by reducing length hospital stays and readmissions. This will ultimately free funding for numerous other healthcare initiatives and programmes, thus improving overall service provided to patients by the NHS. Furthermore, the benefits of the development of such innovative technologies provide benefits to the medical devices industry by the generation of value-added products, allowing the UK to compete effectively in the world market place.