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

慢性伤口，如糖尿病足溃疡（DUF），其特征是愈合速度慢，细菌感染风险高。DFU的溃疡和截肢每年花费NHS约6.5亿英镑，严重损害患者的生活质量。伤口床中细菌生物膜的形成影响愈合时间，因为多种细菌物种存在于这些生物膜内，包括具有多重耐药性（MDR）的病原体。英国公共卫生部的研究人员基于在不同慢性伤口类型中发现的MDR细菌种类建立了复杂的生物膜模型，并证明了抗菌化合物的功效在复杂环境中大大降低，即使对于通常对治疗敏感的细菌也是如此。外源性一氧化氮（NO）作为细菌生物膜分散的信号的潜力引起了相当大的兴趣。值得注意的是，生物膜暴露于NO可能会降低其对抗生素的耐药性，并且NO和抗微生物化合物组合的治疗可以有效地控制生物膜相关感染的进展。在这个项目中，创新的药物将被设计成在超声刺激下以空间和时间控制的方式同时提供NO和抗菌化合物。它们对超声波的响应也将赋予局部机械应力，这预计将显著增加生物活性化合物（即抗生素）穿过生物膜基质的渗透效率。我们预计这些多功能药物将为生物膜相关的MDR慢性感染提供强大的治疗模式，最终有助于提高治疗效果，同时降低给予患者的抗生素浓度。为此，博士候选人将利用实验和计算技术（i）以微粒和纳米颗粒的形式设计超声响应剂，能够共同转运一氧化氮和抗微生物化合物;（ii）确定超声暴露方案以在治疗所需的时间点递送治疗有效载荷，并增强其穿过生物膜基质的渗透;（iii）开发将这种新的治疗方法应用于慢性感染模型的技术;和（iv）临床前验证该方法相对于常规的基于抗肿瘤的治疗的治疗潜力。博士候选人将与英国公共卫生（PHE）的合作伙伴密切合作，并在工程和物理科学，医学和国家生物膜创新中心（NBIC）的高度多学科环境中工作。

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).