Exploiting bacterial virulence to trigger antimicrobial release from orthopaedic implants

2017年，在英格兰和威尔士，由于髋关节和膝关节置换术失败，进行了15091例手术。虽然假体松动是失败的主要原因，但感染仍然是一个主要问题，在这些手术中，感染占2865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，这一数字预计还会上升。感染的关节置换术更复杂，治疗费用也更昂贵，需要更长的手术和住院时间，而且经常有更高的反复失败的风险。这会增加发病率，从而严重影响患者的生活质量，在严重的情况下还可能导致截肢或死亡。很少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；然而，只有低浓度到达植入部位。涂层试图实现抗生素在局部的长期释放；然而，长期接触抗生素会引起毒性问题，甚至会导致抗生素耐药性。其他技术，如种植体表面处理或拓扑学，只能减缓细菌附着，并不能完全消除问题。显然，我们需要更智能、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药物。这个概念利用了金黄色葡萄球菌（一种引起关节置换术感染的细菌）释放一种被称为α溶血素的孔状蛋白质的事实。这种蛋白质将自身插入细胞膜，导致细胞渗漏和死亡。植入物涂层由与细胞膜相同的分子组成，但其内部含有抗菌剂储存库。当细菌释放α溶血素时，会在种植体涂层内形成孔，释放抗菌药物，从而局部根除感染。三个关键目标已经确定，以实现该项目的目的：目标1：优化和表征涂层，以最大限度地触发抗菌药物释放。目的2：扩大包衣工艺规模，评价包衣的抗菌活性和毒性。目的3：评估涂层在更相关的骨感染模型中的性能。与现有的试图刺激反应的涂层不同，当细菌存在时，这种涂层会对环境产生反应。使用这种方法，抗菌药物的释放量将与细菌的数量和产生的α溶血素的数量成正比。因此，这种触发输送系统有潜力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，感染也构成了主要问题。这个项目也有可能引领一个全新的研究领域，利用细胞和细菌的特性来开发更智能、更有效的植入物涂层和靶向药物输送系统。

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.