Within the last decade, therapeutic ultrasound has seen remarkable clinical success expanding into a wide diversity of applications, including cancer therapy, blood-brain barrier opening, and more recently, neuromodulation. While initial applications of therapeutic ultrasound were focused on enhancing cytotoxic effects through ablation or mechanical tissue fractionation, recent efforts in the field have moved towards developing therapeutic strategies that can augment existing processes within the body, most notably in modulating the immune system to help fight disease. My research group will leverage advanced image and signal processing techniques, computational simulations, and physiologically relevant models to uncover how mechanical forces modulate immune responses within a variety of tissue microenvironments.
Contrast-enhanced ultrasound (CEUS) is an imaging modality that enables visualization of blood perfusion with high temporal resolution and without the use of ionizing radiation. In the presence of an ultrasound wave, ultrasound contrast agents (microbubbles) undergo volumetric oscillations that provide nonlinear signal for contrast enhancement or violent micromechanical forces upon exposure to sufficiently large acoustic pressures that can be harnessed therapeutically. My group will develop novel contrast agents for imaging and therapy, and new methodology for improved contrast imaging & cavitation-mediated treatments.
Relevant publications:
B Lyons, JPR Balkaran, D Dunn-Lawless, V Lucian, SB Keller, C O‘Reilly, L Hu, J Rubasingham, M Nair, R Carlisle, E Stride, M Gray, CC Coussios. “Sonosensitive cavitation nuclei - A customisable platform technology for enhanced therapeutic delivery.” Molecules, 2023, 28(23), 7733
SB Keller, TY Lai, MA Averkiou. “Investigation of the phase of the fundamental component of nonlinear echoes during amplitude modulation.” IEEE Trans Ultrason Ferroelectr Freq Control, 2022 Mar;69(3):1032-1040
A unique aspect of ultrasound is that it is one of the few truly “all-in-one” imaging modalities that can be integrated into every aspect of a non-invasive therapy: it can enable diagnostic imaging for precise targeting, deliver high-energy acoustic waves for treatment, and allow real-time monitoring of cavitation emissions to assess therapeutic safety and/or success. My group will design new schemes of image-guided intervention in which ultrasound contrast imaging, cavitation-mediated therapeutic ultrasound, and cavitation imaging can all be interleaved into a single control system that is automated and user-independent.
Relevant publications:
SB Keller, G LuTheryn, B Lyons, M Gray, RO Cleveland, E Stride, CC Coussios,. “Spatiotemporal evaluation of anti-biofilm cavitation activity by passive acoustic mapping.” Phys. Med. Biol, 2024, 69, 215008
SB Keller, PS Sheeran, MA Averkiou. “Cavitation therapy monitoring of commercial microbubbles with a clinical scanner.” IEEE Trans Ultrason Ferroelectr Freq Control, 2021 Apr;68(4):1144-1154
SB Keller, D Suo, Y-N Wang, H Kenerson, RS Yeung, MA Averkiou. “Image-Guided Treatment of Primary Liver Cancer in Mice Leads to Vascular Disruption and Increased Drug Penetration.” Front. Pharmacol. 2021. 11:584344. doi: 10.3389/fphar.2020.584344
Biofilms are sessile communities of microbes that promote both physical and functional changes that protect bacteria from their environment. Additionally, bacterial colonization and impaired immune function frequently coexist, stalling tissue repair and leading to non-healing infections. Non-invasive biofilm debridement with utlrasound is a promising method to improve antibiotic therapies; however, it is still unclear how the maximally effective antibiofilm parameters influence the host immune response or whether dispersed bacteria are effectively cleared by the immune system or persist to form downstream infections. My group will develop in vitro, ex vivo, and in vivo models of bacterial infection as a platform to understand the host response to cavitation-mediated antibiofilm therapies.
Relevant publications:
SB Keller, G LuTheryn, B Lyons, M Gray, RO Cleveland, E Stride, CC Coussios,. “Spatiotemporal evaluation of anti-biofilm cavitation activity by passive acoustic mapping.” Phys. Med. Biol, 2024, 69, 215008
G LuTheryn, C Hind, C Campbell, A Crowther, Q Wu, SB Keller, P Glynne-Jones, JM Sutton, JS Webb, M Gray, SA Wilks, E Stride, D Carugo. “Bactericidal and anti-biofilm effects of uncharged and cationic ultrasound-responsive nitric oxide microbubbles on Pseudomonas aeruginosa biofilms.” Front. Cell. Infect. Microbiol., 2022.
The use of focused ultrasound opens avenues to enhance the host immune response to infection and injury through direct mechanical stimulation of immune cells. To further explore these mechanisms, my group will evaluate ultrasound parameters that induce a variety of biomechanical forces with or without cavitation nuclei (such as shear force, compression, radiation force, or cavitation-induced microjetting) on single cells in suspension and/or spatially isolated within standing waves versus cells seeded within environments with increasing stiffness.
Relevant publications:
O Pattinson, SB Keller, ND Evans, F Pierron, D Carugo. “An Acoustic Device for Ultra High-Speed Quantification of Cell Strain During Cell-Microbubble Interaction.” ACS Biomat. Sci. Eng., 2023, 9, 5912-5923