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Emerging Imaging, Affordable Imaging

Bubble brilliance – how microbubbles provide contrast in ultrasound imaging

Project ID: 2023_033

1st Supervisor: Dr James Choi, Imperial College London
2nd Supervisor: Dr Kirsten Christensen-Jeffries, King’s College London
Academic collaborators: Dr Christopher Rowlands (Optics), Dr Sam Au (Microfluidics), and Dr Andrei Kozlov, (Neuroscience), Imperial College London


Aim of the PhD Project:

To understand how microbubbles provide contrast in ultrasound imaging. Microbubbles are contained in the blood, so we aim for the following:

  • Understand how microbubbles produce signals in in vitro and ex vivo microvessels
  • Understand how to enhance microbubble signals from microvessels
  • Develop a microvessel imaging algorithm


Lay Summary:

Microbubbles are particles administered into the blood that enhance the ultrasound image quality. Normally unviewable diseased regions, such as liver tumours or dead heart tissue, are made visable by the ultrasound signal enhancing role of microbubbles. The source of such bubble brilliance, however, is poorly understood for microbubbles flowing through out tiniest vessels. Questions remain on where the bubble brilliance eminates from. In other words, are the enhanced images pictures of the large vessels only, or are they from the microvasculature? If we can solve this puzzle, then we would have the know-how to improve our images further, creating crisper and smarter images of cancer and heart disease.

The most common microbubbles have a lipid shell and a heavy gas core, making them stable and biologically inert. They are primarily used to diagnose diseases in the liver and heart; but their use is at the cusp of rapid expansion. With microbubbles, traditional limitations with ultrasound imaging are being dismantled by new technologies, such as super-resolution imaging with spatial resolutions below 50 µm and ultrafast imaging with frame rates over 1,000 Hz. These technologies use the enhanced signal of microbubbles to provide incredible images never thought possible by ultrasound.

Although microbubbles are well-described in water their behaviours in blood vessels are not. In water, microbubbles expand and contract to the ultrasound pulse, emitting a unique signal back to the emitter. In a capillary, where nearly all microbubbles flow through, some hypothesise that this signal is damped, because the bubble has less space to expand into. This could lead to changes in the resonance, strength, and shape of the emitted signal. These questions have implications in contrast as all microbubble signals comes from within vessels, and it is unclear how the signal differs in different sized vessels.

So far, all hypothetical explanations for how microbubbles behave in capillaries have been untested; because no one has found a way to observe microbubble oscillations in capillaries. Microbubbles oscillate at millions of times per second and in capillaries that are embedded in opaque tissue.

In preliminary data, we produced the first direct observations of microbubbles oscillating in capillaries (Figure 1). To achieve this, we invented two transparent capillary models – an in vitro phantom and ex vivo brain slice – and observed the microbubble’s oscillations with a microscope and high-speed camera.

In the proposed PhD project, the student will use our unique experimental platform to study ultrasound contrast in capillaries and other microvessels. The student will begin by learning how to extract and preserve slices of rat brains (ex vivo model) and create micron-sized capillaries in hydrogels (in vitro model). The microbubbles will be exposed to ultrasound while capturing its radial oscillations and listening to the sound that they emit. The optical and acoustic data will be analysed to explain how microbubbles oscillate and provide contrast in microvessels. We will then develop a microvascular imaging algorithm that boosts signals from microvessels. This will include super-resolution methods (Figure 2) and other novel techniques.

By providing the first mechanistic understanding of how microbubbles provide contrast in microvessels, we hope to inspire technologies that will can image the microvasculature and differentiate its many parts.

We are seeking PhD applicants with a background in engineering or physics.

First optical image of a microbubble in a capillary. See below for further description.

Figure 1. First optical image of a microbubble in a capillary. A transparent brain slice was extracted from rat pups and immersed in cerebrospinal fluid. The microbubble has a diameter of 4 µm [preliminary data].

Conventional and super-resolution ultrasound imaging.

Figure 2. Conventional and super-resolution ultrasound imaging. (A) Conventional contrast-enhanced ultrasound image of a rat ear with microbubbles injected. (B) Super-resolution achieves resolutions as fine as 19µm. It is unclear why arteries and veins appear, but not capillaries. Scale bar: 1 mm. Image from Christensen-Jeffries et al, IEEE transactions on medical imaging 2014.



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