Multifunctional agents for ultrasound-mediated treatment of biofilms in chronic infections

慢性伤口，如糖尿病足部溃疡(DUF)，其特点是愈合速度慢，细菌感染的风险很高。DFU的溃疡和截肢每年花费NHS约6.5亿GB，并严重影响患者的生活质量。伤口床上细菌生物膜的形成会影响愈合时间，因为这些生物膜内有多种细菌，包括具有多重耐药性(MDR)的病原体。英国公共卫生的研究人员根据在不同慢性伤口类型中发现的多药耐药细菌种类建立了复杂的生物膜模型，并证明了抗菌化合物在复杂环境中的有效性大大降低，即使是对通常容易治疗的细菌也是如此。外源一氧化氮(NO)作为细菌生物膜扩散的信号的潜力引起了人们极大的兴趣。值得注意的是，生物膜暴露在NO中可能会降低它们对抗生素的耐药性，而NO和抗菌化合物的联合治疗可能有效地控制与生物膜相关的感染的进展。在这个项目中，创新的试剂将被设计成在超声波刺激下以空间和时间控制的方式同时提供NO和抗微生物化合物。它们对超声波的反应还会产生局部机械应力，这有望显著提高生物活性化合物(即抗生素)在生物膜基质中的渗透效率。我们预计，这些多功能制剂将为生物膜相关的多药耐药慢性感染提供一种强大的治疗方式，最终有助于提高治疗效果，同时减少给患者使用的抗生素浓度。为此，博士候选人将利用实验和计算技术来(I)设计能够共运输一氧化氮和抗微生物化合物的微粒和纳米颗粒形式的超声波响应剂；(Ii)确定超声暴露制度，以在期望的时间点提供治疗有效载荷用于治疗，并增强其在生物膜基质中的渗透性；(Iii)开发技术，将这种新的治疗方法应用于慢性感染的模型；以及(Iv)临床前验证这种方法相对于传统的基于抗生素的治疗的治疗潜力。这位博士生将与英国公共卫生学院(PHE)的合作伙伴密切合作，并在高度多学科的环境中合作，涉及工程和物理科学、医学和国家生物膜创新中心(NBIC)。

Chronic wounds, such as diabetic foot ulcers (DUFs), are characterised by slow healing rates with high risk of bacterial infection. Ulceration and amputation from DFUs cost the NHS approximately £650 million per year and severely compromise a patient's quality of life. The formation of bacterial biofilms in the wound bed impacts on healing times, since multiple bacterial species reside within these biofilms, including pathogens having multiple drug resistance (MDR). Researchers at Public Health England have established complex biofilm models based on MDR bacterial species found in different chronic wound types, and have demonstrated that the efficacy of antimicrobial compounds is much reduced in complex environments, even for bacteria which are usually susceptible to treatment.The potential of exogenous nitric oxide (NO) to act as a signal for the dispersal of bacterial biofilms has attracted considerable interest. Notably, exposure of biofilms to NO may reduce their resistance to antibiotics, and treatments combining NO and antimicrobial compounds may effectively control the progression of biofilm-related infections. In this project, innovative agents will be engineered to simultaneously deliver NO and antimicrobial compounds upon ultrasound stimulation, in a spatially- and temporally-controlled fashion. Their response to ultrasound waves will also impart local mechanical stress, which is expected to significantly increase penetration efficiency of bioactive compounds (i.e. antibiotics) across the biofilm matrix. We anticipate that these multifunctional agents will provide a powerful treatment modality for biofilm-related MDR chronic infections, ultimately contributing towards increasing treatment efficacy whilst reducing the concentration of antibiotics administered to a patient.To this end, the PhD candidate will utilise both experimental and computational techniques to (i) engineer ultrasound-responsive agents in the form of microparticles and nanoparticles, capable of co-transporting nitric oxide and antimicrobial compounds; (ii) identify ultrasound exposure regimes to deliver the therapeutic payload at desired time-points for treatment, and enhance its penetration across the biofilm matrix; (iii) develop technologies to apply this novel treatment method to models of chronic infection; and (iv) pre-clinically validate the therapeutic potential of this method against conventional antibiotic-based treatments. The PhD candidate will work closely with partners at Public Health England (PHE), and within a highly multi-disciplinary environment across the Faculties of Engineering and Physical Sciences, Medicine, and the National Biofilms Innovation Centre (NBIC).