Periodic Reporting for period 1 - MICOMAUS (Sophisticated Microbubble Coating Materials for Functional Ultrasound Sensing)
Période du rapport: 2023-06-01 au 2025-11-30
Ultrasound imaging is the most widely used medical imaging modality, offering real-time, low-risk, and cost-effective diagnostics. Its power can be dramatically enhanced by lipid-coated microbubbles, which act as ultrasound contrast agents (UCAs). Driven by ultrasound, these microbubbles oscillate and emit a strong nonlinear echo, enabling visualization of blood flow and organ perfusion. Beyond imaging, microbubbles hold enormous untapped potential for non-invasive blood pressure sensing and molecular imaging, where functionalized bubbles bind to diseased cells and reveal pathological changes in real time.
However, current UCAs suffer from two fundamental limitations. First, they consist of bubbles that vary widely in size (1–10 μm). Second, even mono-sized bubbles produced by modern microfluidics still show unpredictable and heterogeneous acoustic responses due to uncontrolled shell composition and structure. This non-uniformity prevents precise pressure sensing down to clinically relevant resolutions (5 mmHg) and hinders reliable molecular detection, keeping these game-changing applications out of reach.
The overarching goal of MICOMAUS is to enable the controlled formation of mono-acoustic microbubbles: bubbles that are not only mono-sized but also have a tuned, predictable acoustic response. This breakthrough requires unraveling the complex coupling between microbubble formation, shell rheology, and ultrasound-driven dynamics—spanning fluid dynamics, colloid and interface science, and acoustics. MICOMAUS will combine high-speed, high-resolution experiments, theoretical modeling, and simulations to create a physics-based understanding of how shell formulation, microfluidic parameters, gas exchange, and molecular binding shape the acoustic behavior of bubbles.
By delivering this knowledge and control, the project aims to transform microbubble technology from trial-and-error to predictive design, paving the way for high-precision ultrasound sensing and targeted molecular imaging. These advances promise a major clinical and societal impact: more accurate diagnostics, safer patient monitoring, and ultimately, new frontiers in personalized and non-invasive medicine.
However, current UCAs suffer from two fundamental limitations. First, they consist of bubbles that vary widely in size (1–10 μm). Second, even mono-sized bubbles produced by modern microfluidics still show unpredictable and heterogeneous acoustic responses due to uncontrolled shell composition and structure. This non-uniformity prevents precise pressure sensing down to clinically relevant resolutions (5 mmHg) and hinders reliable molecular detection, keeping these game-changing applications out of reach.
The overarching goal of MICOMAUS is to enable the controlled formation of mono-acoustic microbubbles: bubbles that are not only mono-sized but also have a tuned, predictable acoustic response. This breakthrough requires unraveling the complex coupling between microbubble formation, shell rheology, and ultrasound-driven dynamics—spanning fluid dynamics, colloid and interface science, and acoustics. MICOMAUS will combine high-speed, high-resolution experiments, theoretical modeling, and simulations to create a physics-based understanding of how shell formulation, microfluidic parameters, gas exchange, and molecular binding shape the acoustic behavior of bubbles.
By delivering this knowledge and control, the project aims to transform microbubble technology from trial-and-error to predictive design, paving the way for high-precision ultrasound sensing and targeted molecular imaging. These advances promise a major clinical and societal impact: more accurate diagnostics, safer patient monitoring, and ultimately, new frontiers in personalized and non-invasive medicine.
During this reporting period, the MICOMAUS project achieved significant technical and scientific milestones toward understanding and controlling the acoustic behavior of lipid-coated microbubbles. In this first phase, we have laid the groundwork for the predictive design of mono-acoustic microbubbles by developing advanced experimental tools and generating key reference data.
We developed and refined experimental setups capable of capturing rapid microbubble formation events and their evolving shell microstructures. The use of an innovative high-speed Acoustical Camera enabled detailed quantification of the acoustic variability among microbubbles of the same size. This revealed previously unrecognized heterogeneity in shell viscoelasticity linked to phase-separated lipid domains formed immediately after bubble pinch-off. In parallel, we introduced novel interfacial rheometry techniques to directly measure the surface dilatational elasticity of microbubble shells. This led to the unexpected observation of negative surface tension during shell compression, which challenges existing shell mechanics models and explains bubble growth dynamics under pressure. To improve measurement precision, we developed optical attenuation spectroscopy (OAS) for rapid, label-free sizing of monodisperse microbubble suspensions with sub-100 nm accuracy. This tool provides essential input parameters for theoretical models and bubble design optimization. Using these tools, we demonstrated methods to enhance microbubble stability against overpressure through controlled post-production heating, which expels emulsifier lipids and strengthens the shell. Additionally, doping the shell with palmitic acid increased shell elasticity, improving the nonlinear acoustic response critical for pressure sensing applications. We also advanced automated production facilities for functionalizing microbubbles with targeting ligands, maintaining bubble monodispersity and acoustic properties. First results show that microbubble dynamics change significantly upon specific binding to target surfaces compared to freely floating or non-specifically attached bubbles, opening new possibilities for acoustic discrimination in molecular ultrasound imaging.
Overall, our integrated experimental and theoretical efforts have delivered unprecedented insights into microbubble formation, shell mechanics, and boundary interactions. These advances provide a solid foundation for transitioning from empirical design toward predictive control of microbubble acoustics, which is essential for realizing next-generation ultrasound diagnostics and therapeutics.
We developed and refined experimental setups capable of capturing rapid microbubble formation events and their evolving shell microstructures. The use of an innovative high-speed Acoustical Camera enabled detailed quantification of the acoustic variability among microbubbles of the same size. This revealed previously unrecognized heterogeneity in shell viscoelasticity linked to phase-separated lipid domains formed immediately after bubble pinch-off. In parallel, we introduced novel interfacial rheometry techniques to directly measure the surface dilatational elasticity of microbubble shells. This led to the unexpected observation of negative surface tension during shell compression, which challenges existing shell mechanics models and explains bubble growth dynamics under pressure. To improve measurement precision, we developed optical attenuation spectroscopy (OAS) for rapid, label-free sizing of monodisperse microbubble suspensions with sub-100 nm accuracy. This tool provides essential input parameters for theoretical models and bubble design optimization. Using these tools, we demonstrated methods to enhance microbubble stability against overpressure through controlled post-production heating, which expels emulsifier lipids and strengthens the shell. Additionally, doping the shell with palmitic acid increased shell elasticity, improving the nonlinear acoustic response critical for pressure sensing applications. We also advanced automated production facilities for functionalizing microbubbles with targeting ligands, maintaining bubble monodispersity and acoustic properties. First results show that microbubble dynamics change significantly upon specific binding to target surfaces compared to freely floating or non-specifically attached bubbles, opening new possibilities for acoustic discrimination in molecular ultrasound imaging.
Overall, our integrated experimental and theoretical efforts have delivered unprecedented insights into microbubble formation, shell mechanics, and boundary interactions. These advances provide a solid foundation for transitioning from empirical design toward predictive control of microbubble acoustics, which is essential for realizing next-generation ultrasound diagnostics and therapeutics.
MICOMAUS has already delivered beyond state-of-the-art and even groundbreaking insights into the precise control of microbubble acoustic behavior by combining advanced experimental techniques with theoretical modeling. These results surpass current understanding by revealing fundamental mechanisms of shell formation, rheology, and binding effects, enabling the first steps toward predictable and uniform ultrasound contrast agents. This sets the stage for transformative applications in high-precision medical imaging and non-invasive diagnostics.