Predicting how microbubble carriers will behave under the influence of ultrasound is clearly an important part of the equation. The trouble is, existing models of microbubble dynamics do not match genuine clinical scenarios, according to researchers from the University of California, Davis in the US. Streams of oscillating microbubbles can make blood-vessel walls flex too. Yet most calculations picture the bubbles in an infinite liquid, say Shengping Qin and Katherine Ferrara. Other models envisage vessels as rigid tubes that are far wider than individual microbubbles. Neither scenario captures the reality of 0.5–5 µm diameter bubbles travelling rapidly through flexible, blood-filled microvessels that could be just 15 µm wide.
Qin and Ferrara have instead devised a "lumped parameter" model that takes account of interactions between oscillating microbubbles and compliant microvessels (Phys. Med. Biol. 51 5065). The significance of vessel-wall behaviour is only just emerging, according to Ferrara. Experimental studies have indicated that microbubble oscillation can enhance vascular permeability, an effect that could improve the efficiency of drug and gene delivery. However, researchers need to be sure that any unwanted, permanent damage to vessels would be kept to a minimum.
"You can look at things like viscosity, elasticity and other specific effects as a set of parameters and try to evaluate individual effects separately. The alternative, as explored here, is to combine everything together," Ferrara told medicalphysicsweb.
Data from the new model showed that 0.2 MPa peak negative pressure (PNP) and a centre frequency of 1 MHz were sufficient to burst oscillating microbubbles in all compliant vessels 8 µm or wider. In rigid vessels, the bubbles could not be guaranteed to burst even at 0.5 MPa PNP and 1 MHz. However, the model predicted vascular rupture in small (≤15µm) compliant vessels at 0.5 MPa PNP and 1 MHz.
Numerical modelling also revealed a stronger link between centre frequency and the bubbles' circumferential stress. This supports observations from ongoing experimental work at UC Davis, said Ferrara.
The new model should help researchers investigate specific clinical scenarios. For instance, the development of a tumour can increase the rigidity of nearby blood vessels. As a result, conditions required to burst drug-filled capsules or to rupture microvessels may be very different in tumours compared with healthy tissue. Microbubbles designed to transport "clot-busting" drugs may also need to account for vessels stiffened by arterial plaques.
"I don't think any vessel is completely rigid or completely compliant. But before we haven’t really known what the reality was," Ferrara said. "People have done static-pressure measurements with fluids and measured the resulting vessel expansion. What happens here is so different because the microbubbles are moving at hundreds of metres per second at least."
Researchers will also need to consider the size of blood vessels being targeted, the microbubbles' resting diameter and the intended impact of oscillating bubbles. A degree of vascular damage, for instance, may be essential in certain applications but only tolerated in others.
The dependence of microbubbles' behaviour on vessel size and stiffness makes it critical to verify what actually happens in practice, Ferrara says. She recommends using a second imaging modality to monitor the impact of ultrasound-assisted therapy delivery. "The key to success in the clinic is being able to carefully control what you are doing, but also having some feedback that tells you whether or not you are having the desired effect," she added.