ETH Zurich researchers have explored how minuscule gas bubbles can deliver drugs into cells precisely using ultrasound technology. For the first time, they’ve visualized how tiny liquid jets produced by microbubbles pierce through cell membranes and facilitate drug uptake. Targeting brain diseases like Alzheimer’s, Parkinson’s, or tumors is particularly challenging due to the brain’s sensitive nature and robust defenses. This has led researchers to develop methods for delivering drugs directly into the bloodstream as a means of overcoming the blood-brain barrier.
Microbubbles that respond to ultrasound are considered a promising method in this type of therapy. These microbubbles, smaller than red blood cells and filled with gas, have special fat-based coatings that stabilize them. They are administered into the bloodstream alongside drugs and activated at the desired target site using ultrasound waves. The motion of these microbubbles creates small pores in the cell membranes lining blood vessels, allowing drugs to pass through.
The exact mechanism by which microbubbles create these pores was previously unknown. Recently, a group led by Professor Outi Supponen from ETH Zurich’s Institute of Fluid Dynamics has elucidated this process for the first time. “We demonstrated that under ultrasound conditions, the surface of microbubbles loses its shape and generates tiny jets of liquid called microjets,” explains Marco Cattaneo, Supponen’s doctoral student and lead author on a study recently published in Nature Physics.
These invisible forces are so powerful; they can move at speeds of up to 200 km/h. Previously, the formation of pores in cell membranes remained unexplained due to the minuscule size—just a few micrometers across—of microbubbles and their rapid vibration rates under ultrasound waves (up to several million times per second). Observing this phenomenon is incredibly challenging and requires specialized lab equipment.
“Most studies have traditionally viewed the process from above using conventional microscopes,” says Cattaneo. “But that approach doesn’t allow us to see what’s happening between the microbubble and the cell.” To overcome these limitations, researchers created a microscope with 200x magnification capable of observing the interaction side-on and linked it to high-speed cameras taking up to ten million images per second.
For their experiments, they used an in-vitro model where endothelial cells were grown on a plastic membrane. This membrane was placed inside a transparent box filled with saline solution and model drugs; the cells faced downward like lids. The gas-filled microbubble rose automatically to the top and made contact with the cells. Following this, it was activated by a brief ultrasound pulse.
At sufficiently high ultrasound pressures, microbubbles cease oscillating in their spherical shape and start reshaping themselves into regular non-spherical patterns. These patterns’ “lobes” oscillate cyclically—alternately folding inward and outward. The researchers discovered that above a certain threshold pressure, these inward folds can deepen to create powerful jets that traverse the entire bubble, touching the cell.
These microjets move at an incredible 200 km/h speed, capable of piercing cell membranes without damaging them. Importantly, this jet mechanism doesn’t destroy the bubble itself; it allows for a new microjet formation with each ultrasound cycle. Supponen notes that “an intriguing aspect is that this ejection mechanism is triggered by low ultrasound pressures—around 100 kPa.” This means the pressure exerted on microbubbles and patients would be comparable to normal atmospheric air pressure.
In addition to visual observations, researchers employed various theoretical models to explain these findings. They concluded that among other proposed mechanisms, the microjet method holds the highest potential for causing damage, strongly supporting their observation of how cell membranes are pierced when such jets form. Cattaneo mentions that “with our lab setup, we now have a better way of observing microbubbles and can describe their interaction with cells more precisely.” This system could also be used to study how other researchers’ new microbubble formulations react to ultrasound.
Supponen elaborates, stating that “our work clarifies the physical foundations for targeted drug delivery using microbubbles and helps us define criteria for their safe and effective use.” By optimizing frequency, pressure, and bubble size, therapists can enhance therapy outcomes while ensuring greater safety and reduced risk to patients. Additionally, researchers could refine the coating of microbubbles to match required ultrasound frequencies more easily.
