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，以及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NHS产生重大后果。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)的医疗器械(如导管)的使用现在已成为各种临床环境中的常规和频繁使用。尽管使用内置式医疗器械有很大的好处，但据报道，潜在严重并发症的发生率高得令人担忧。一般来说，与插入医疗设备相关的并发症会导致患者在医院停留的时间增加，再次入院，在非常严重的情况下，患者死亡人数增加。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，细菌或真菌在设备表面生长，形成一个名为生物膜的“受保护群落”。一旦设备上形成了生物膜，在不移除设备的情况下，一旦感染得到治疗，就非常困难。根据医疗器械位置的不同，这可以是简单的(尿路)，如果不舒服和不方便，可能需要进行严重和危及生命的手术(如静脉导管或心脏假体)。使用插入式医疗器械的这一方面对于原本是高效、有益且通常是简单的医疗治疗来说是最严重和关键的缺点。显然，迫切需要通过开发积极抵抗和预防感染的新型和创新的医疗器械来改善目前的状况，从而减少与医疗器械相关的感染的发生率。这项研究建议的主要目标是通过开发新的创新材料来应对通过释放抗生素而感染微生物的存在，从而提高需要这种医疗设备的患者的有效性和生活质量。在感染期间，细菌使用非常特殊的酶来分解周围的组织蛋白质和其他分子。该项目旨在利用这些非常特殊的蛋白质切割酶，即蛋白酶，来激活新型设备涂层中的抗生素释放。这样，在设备相关感染的发展过程中，只有在感染细菌存在的情况下，抗生素分子才会释放。抗生素将在设备表面积累到杀死感染细菌所需的浓度，从而保护设备，并最终保护患者免受相关感染。因此，抗生素的释放与感染微生物的存在相协调，因此该装置不会永久地释放药物/这一情况很难长期保持，而且这一特征已被证明会导致出现耐药细菌，如MRSA。该项目的主要成果是通过改善植入医疗器械的抗菌活性和寿命，改善依赖于植入医疗器械的治疗的患者的高度不满意的状况。该项目还将通过减少住院时间和再入院时间来降低与这种医疗相关的成本，从而为NHS带来明显的好处。这最终将腾出资金用于许多其他医疗倡议和计划，从而改善NHS为患者提供的整体服务。此外，这些创新技术的发展带来的好处通过产生增值产品而为医疗器械行业带来好处，使英国能够在世界市场上有效地竞争。

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.