ETH Zurich Researchers Uncover the Mechanism of Microbubble-Driven Drug Delivery Systems

Researchers from ETH Zurich have made groundbreaking discoveries regarding how tiny gas bubbles can deliver drugs into cells using ultrasound technology in a targeted manner. For the first time, they’ve visualized how liquid jets generated by microbubbles penetrate cell membranes, enabling drug uptake.

Treating brain diseases like Alzheimer’s, Parkinson’s, or brain tumors poses significant challenges due to the brain’s sensitivity and strong protection from substances found in blood—a barrier that only allows certain nutrients and oxygen through. This is why researchers are developing methods for precise drug delivery directly into the brain via the bloodstream. Microbubbles that respond to ultrasound show particular promise as they can overcome this barrier.

These microbubbles, smaller than a red blood cell and filled with gas, have special fat molecule coatings to maintain stability. When injected along with drugs into the bloodstream and activated by targeted ultrasound at specific sites within the body, these bubbles cause slight changes in vessel walls’ membranes that allow drug passage without harming surrounding tissue.

Until now, scientists were uncertain about exactly how microbubbles create those tiny pores in cell membranes through which drugs can enter. However, a team led by Professor Outi Supponen from ETH Zurich’s Institute of Fluid Dynamics has shed light on this mechanism. According to Marco Cattaneo, the professor’s doctoral student and lead author of their study published recently in Nature Physics, “We demonstrated that when activated with ultrasound, microbubbles lose their spherical shape, generating tiny liquid jets called microjets which penetrate cell membranes.”

The action occurs rapidly: these invisible forces shoot through at speeds reaching 200 kilometers per hour. Observing this phenomenon has been incredibly difficult because of the minute size (just a few micrometers) and rapid vibrations (up to several million times per second) under ultrasound.

Most past research used conventional microscopes for viewing from above, unable to capture what happens between the bubble and cell membrane due to limitations in imaging technology. The team developed an advanced microscope with 200x magnification that allows them to view this process sideways and connected it to a high-speed camera capable of up to ten million images per second.

They created an experimental setup mimicking blood vessel walls using cultured endothelial cells on transparent plastic membranes placed in boxes filled with saline solutions containing model drugs. Gas-filled microbubbles rose automatically, coming into contact with the cell layer facing down like a lid. Then, after applying an ultrasound pulse lasting just microseconds at high pressure—enough to break their spherical shape and cause them to oscillate non-spherical patterns—the inward-folding ‘lobes’ of these patterns would sink deeply enough to create powerful microjets that crossed through entire bubbles before making contact with the cell membrane.

This ejection mechanism is activated even under relatively low ultrasound pressures, around 100 kPa. Professor Supponen explained: “The pressure acting on the microbubbles and hence patients during treatment would be comparable to normal atmospheric air pressure.” The team used both experimental observations and theoretical models to demonstrate that these liquid jets have a significant potential for causing damage among all other proposed mechanisms, thereby supporting their findings about how cells are perforated only when microjets form.

With this improved lab setup, the researchers can more accurately observe interactions between microbubbles and cell membranes. This system may also be utilized to investigate responses of newly developed bubble formulations by other research groups under ultrasound conditions.

This work clarifies physical foundations for targeted drug delivery via microbubbles and sets criteria for their safe and effective application in medical treatments, optimizing factors such as frequency, pressure levels, and microbubble sizes. It has been demonstrated that only a few pulses of ultrasound are required to perforate cell membranes—another positive outcome beneficial to patients.

Moreover, the outer coatings of these microbubbles can also be adjusted for specific frequencies required by the jets’ formation process. Such advancements underscore how understanding physics underlies effective medical therapies and could significantly improve treatment outcomes with minimal risks for patients.