Exploiting bacterial virulence to trigger antimicrobial release from orthopaedic implants

利用细菌毒力触发骨科植入物释放抗菌剂

• 批准号: EP/T016124/1
• 负责人: Wayne Nishio Ayre
• 金额: $ 33.67万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FT016124%2F1
• 关键词: Exploiting; bacterial; virulence; trigger; antimicrobial

In England and Wales in 2017, 15,091 surgeries were performed due to failed hip and knee replacements. Although loosening of the implant is the main cause of failure, infection still remains a major problem, accounting for 2,865 of these procedures and over £73 million in annual costs for the NHS. This number is expected to rise with an ageing population and the number of joint replacement surgeries increasing annually.Infected joint replacements are more complicated and costly to treat, requiring longer surgical and hospital inpatient times, and are often at a higher risk of repeated failure. This significantly affects patient quality-of-life through increased morbidity and in severe cases it can also result in amputation or death. Few commercial technologies exist to prevent this problem. Often oral or intravenous antibiotics are used; however only low concentrations reach the implant site. Coatings attempt to achieve a prolonged local release of antibiotics; however long-term exposure to antibiotics can cause toxicity issues or even encourage antibiotic resistance. Other technologies such as implant surface treatments or topographies, only slow down bacterial attachment and do not eliminate the problem entirely. There is clearly a need for smarter, more effective technologies to prevent infections in orthopaedics.This project aims to achieve this by developing a novel smart implant coating that only releases an antimicrobial in the presence of bacteria. The concept exploits the fact that Staphylococcus aureus, a bacterium that causes joint replacement infections, releases a pore-shaped protein known as alpha-haemolysin. This protein inserts itself in cell membranes causing leakage and cell death. The implant coating consists of the same molecules as cell membranes however it contains a reservoir of antimicrobial within it. When the bacteria release alpha-haemolysin, this creates pores within the implant coating, releasing the antimicrobial and eradicating the infection locally. Three key objectives have been identified to achieve the aim of this project:Objective 1: Optimise and characterise the coating to maximise triggered antimicrobial release.Objective 2: Scale up the coating process and evaluate the antimicrobial activity and toxicity of the coating.Objective 3: Evaluate the performance of the coating in a more relevant bone infection model.Unlike existing coatings, which attempt to stimulate a response, this coating will react to the environment when bacteria are present. Using this approach, the amount of antimicrobial released will be proportional to the number of bacteria and the amount of alpha-haemolysin produced. This triggered delivery system therefore has the potential to overcome numerous issues with existing technologies. Outside of orthopaedics, this technology would have numerous applications, for example in dental and maxillofacial implants and ophthalmic and cardiovascular medical devices, where infections also pose major problems. This project also has the potential to lead to a completely new area of research, where cell and bacterial characteristics are exploited to develop smarter, more effective implant coatings and targeted drug delivery systems.

2017年，英格兰和威尔士因髋关节和膝关节置换术失败而进行了15，091次手术。虽然植入物松动是失败的主要原因，但感染仍然是一个主要问题，占这些手术的2，865例，NHS每年的费用超过7300万英镑。随着人口老龄化和关节置换手术数量的逐年增加，这一数字预计将上升。感染的关节置换手术更复杂，治疗成本更高，需要更长的手术和住院时间，并且经常有更高的重复失败风险。这通过增加发病率显著影响患者的生活质量，在严重情况下，还可能导致截肢或死亡。几乎没有商业技术可以防止这个问题。通常使用口服或静脉注射抗生素;但只有低浓度到达植入部位。涂层试图实现抗生素的长期局部释放;然而，长期暴露于抗生素可能导致毒性问题，甚至鼓励抗生素耐药性。其他技术，如植入物表面处理或形貌，只能减缓细菌附着，并不能完全消除问题。显然，需要更智能、更有效的技术来预防骨科感染。该项目旨在通过开发一种新型智能植入物涂层来实现这一目标，该涂层仅在细菌存在时释放抗菌剂。这个概念利用了一个事实，即金黄色葡萄球菌，一种引起关节置换感染的细菌，释放一种称为α-溶血素的孔状蛋白质。这种蛋白质插入细胞膜，导致渗漏和细胞死亡。植入物涂层由与细胞膜相同的分子组成，但其中含有抗菌剂。当细菌释放α-溶血素时，这会在植入物涂层内产生孔隙，释放抗菌剂并局部根除感染。为实现本项目的目标，确定了三个关键目标：目标1：优化和优化涂层，以最大限度地触发抗菌剂释放。目标2：扩大涂层工艺并评估涂层的抗菌活性和毒性。目标3：在更相关的骨感染模型中评估涂层的性能。与试图刺激反应的现有涂层不同，当存在细菌时，该涂层将对环境起反应。使用这种方法，释放的抗菌剂的量将与细菌的数量和产生的α-溶血素的量成比例。因此，这种触发输送系统有可能克服现有技术的许多问题。在整形外科之外，这项技术将有许多应用，例如在牙科和颌面植入物以及眼科和心血管医疗设备中，感染也是主要问题。该项目也有可能导致一个全新的研究领域，利用细胞和细菌特性开发更智能，更有效的植入涂层和靶向药物输送系统。

项目成果

The development of a responsive supported lipid bilayer coating to prevent uncemented joint replacement infections

开发响应性支撑脂质双层涂层以预防非骨水泥关节置换感染

• 发表时间: 2023
• 作者: Azizova L

Development of an antimicrobial lipid coating to prevent infections in uncemented joint replacements

开发抗菌脂质涂层以预防非骨水泥关节置换术中的感染

• 发表时间: 2023
• 作者: Azizova L

Parameters controlling octadecyl phosphonic acid self-assembled monolayers on titanium dioxide for anti-fouling biomedical applications

• DOI: 10.1016/j.apsusc.2022.154462
• 发表时间: 2022-08-11
• 期刊: APPLIED SURFACE SCIENCE
• 影响因子: 6.7
• 作者: Azizova，Liana;Morgan，David;Ayre，Wayne Nishio
• 通讯作者: Ayre，Wayne Nishio