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

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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).