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Targeted microbubble vibrations to accurately diagnose and treat cardiac device-related bacterial biofilm infections

Periodic Reporting for period 3 - BUBBLE CURE (Targeted microbubble vibrations to accurately diagnose and treat cardiac device-related bacterial biofilm infections)

Reporting period: 2022-01-01 to 2023-06-30

Due to an aging population, increasingly more cardiac devices are implanted (pacemaker/ICD/CRT/ prosthetic valve/LVAD; worldwide ~2 million yearly). Life-threatening bacterial infections (1-60% infection and 29-50% mortality rate) associated with these devices are a major healthcare burden and pose scientific challenges. Ultrasound imaging is currently the primary diagnostic modality. However, it lacks specificity and sensitivity because the signal from the bacteria is similar to the signal of healthy tissue or the cardiac device, thus making accurate diagnosis impossible. Recent developments in targeted ultrasound contrast agents (i.e. targeted microbubbles (tMB), 1-8 micron in size) allow ultrasound imaging of a specific tMB vibration signal resulting in exceptional sensitivity and specificity. Advancing tMB imaging to detect bacterial infections is needed to solve the challenges caused by the complex ultrasound field from these devices. I was the first to show that vibrating tMB induce vascular drug uptake, thereby showing the potential of tMB as a theranostic agent by combining imaging with drug delivery. Recently, my team and I were also the first to demonstrate which tMB vibrations kill vessel wall cells in vitro by developing analysis methods that link tMB vibrations to drug uptake patterns on a single cell layer. As this is the first time this technique will be applied to 3D bacterial biofilm infections on cardiac devices, I will go beyond the state-of-the-art in tMB-tissue interaction technology by developing novel detection, analysis, and modeling methods to accurately determine which tMB vibrations eradicate bacterial biofilm infections on devices.
The Bubble Cure project will result in a novel multidisciplinary technology that allows accurate diagnosis and treatment of cardiac device-related bacterial biofilm infections, thereby creating a whole new direction of tMB ultrasound imaging and therapy in the scientific field of cardiology and microbiology.
For the development of novel targeted microbubbles that can specifically bind to bacterial biofilms, the antibiotic vancomycin was successfully coupled to the shell of microbubbles. These microbubbles are 4 micrometer in size, which is similar to the size of a red blood cell. The ability of these vancomycin-decorated microbubbles to bind to biofilms grown in the laboratory was assessed and compared with control microbubbles not containing vancomycin. Significantly more vancomycin-decorated microbubbles than control microbubbles bound to the bacterial biofilms both in static and under physiological flow conditions. Using a commercially available ultrasound machine, the vancomycin-decorated microbubbles that had bound to the biofilm were shown to generate a specific echogenic signal, thereby proving that the microbubbles can be visualized with ultrasound supporting its value in a diagnostic setting. Furthermore, the biofilms grown in the laboratory were treated with ultrasound and the vancomycin-decorated microbubbles. Upon ultrasound application, the vancomycin-decorated microbubbles reduced the amount of biofilm by ~20%.
A novel vancomycin-decorated microbubble was successfully produced that has great potential for both detecting and treating the biofilm using ultrasound. Development of detecting and treating the vancomycin-decorated microbubbles using ultrasound will continue beyond the first proof-of-concept. Since these microbubbles are a theragnostic agent, we expect to be able to diagnose and treat more complex bacterial biofilms which mimic the bacterial infections on cardiac devices at the end of the project.