Super resolution ultrasound localization microscopy – is it ready to be incorporated into clinical practice?

Super resolution ultrasound (SRUS) through localizing and tracking contrast agents, also known as ultrasound localization microscopy (ULM), has demonstrated the ability to visualize sub wavelength structures in vivo a decade ago [1] [2].

Ultrasound image resolution faces a limit, inherent to all wave-based imaging processes, where diffraction of the transmitted and received waves means that point sources become indistinguishable from one another when closer than approximately half the transmitted wavelength. Beyond this, interference of scattered sound results in acoustic speckle. Thus, similar to optical super-resolution imaging which utilizes sparsely switched fluorescence molecules to provide the individual signal sources required, ultrasound contrast agents were proposed for ULM. The resolution of the imaging system is thus close to the size of the microbubble and capillaries, but it is important to note that the microbubbles are not the structure to be imaged, but they are rather the probes that highlight the particular structure. These methods thus allow vascular structures to be resolved below the diffraction limit, and typical resolutions in the range of down to a tenth of the wavelength can be achieved.

The ultrasound super-resolution process requires the introduction of a contrast agent into the body. Akin to its optical counterpart, it also needs the acquisition of a sequence of frames. A crucial principle within localization microscopy techniques is that by limiting the number of sources detected in each image, the responses of individual agents do not interfere with each other. Under this constraint, the location of the underlying scatterers, in this case, microbubbles, can be estimated to a precision far higher than the diffraction-limited resolution of the system. Super-resolution ultrasound imaging has seen a flurry of technical advances [3] [4] [5] and can achieve resolution down to ~10 micrometres. One of the rate-limiting factors is tissue motion and there have been several techniques utilized to account for this, such as the phase-correlation of rigid tissue motion [6] and implementation of more advanced non-rigid motion correction, taking into account complex motions within the image [7].

Recent advances now allow 3D super resolution to be achieved, which is capable of depicting the microvasculature of a volume, or even the entire organ, within one microbubble bolus [8] [9] [10] [11] [12].

ULM enables novel quantitative measures of the microvascular morphology and function such as the relative blood volume, vessel size, flow velocity distributions, vessel density, vascular branching and tortuosity, to name a few functional parameters which can now be more accurately measured.

ULM is thus of potential interest for pathologies and changes that are related to the morphology or physiology of the microvasculature [13]. These range from pathologies related to angiogenesis in neoplasms or inflammation, or conditions that show a change in microvascular flow. The characterisation of neoplasms where breast malignancy is a good test bed [14] for such technologies – as well as providing parameters which would be useful for the monitoring of tumour response to treatment [15] – are one of the clinical areas which ULM may excel in.

There has also been interest in depicting the microvasculature changes in metastatic lymph nodes where it is known that the microvasculature alters with metastatic infiltration [16] [17].

The ULM techniques have also been shown valuable in depicting the microvasculature of brain [2], heart [18], kidneys [19], and muscles [7], predominantly in animal models where disease processes of these organs in human studies are currently being explored and awaiting translation into routine clinical practice [7] [10] [13] [14] [17] [19] [23] [24] [25] [26] [27] [28] [29] [30] [31]. The microvasculature also changes with chronic liver disease shown with microflow imaging technology [20], but ULM may allow quantification of these changes non-invasively and more accurately, leading to improved characterization of the degree of fibrosis and inflammation in conjunction with liver stiffness measurements using shear wave elastography technologies.

One remaining limitation, hindering its current clinical use, are the relatively long acquisition times in the order of up to 15 minutes as well as the post-processing elements in order to obtain the useful functional data. These, however, will only improve – and this is now being incorporated into clinical scanners which purportedly are able to provide these parameters within minutes of acquisition, although their accuracy and validity have yet to be determined.

There have also been other proposed techniques utilising nanodroplets rather than microbubbles where faster and selective super-resolution imaging can be achieved [21] [22] as well as the question whether the same information can be obtained from Doppler microvasculature imaging techniques.

The availability and potential of ULM has only just come to the clinical front, and it will likely take several years before data from translational studies are available to demonstrate its clinical value, including the added value over Doppler microvascular imaging technologies and CEUS, prior to its incorporation into routine clinical use. It thus currently remains in the research field but is very much at the forefront of advances in ultrasound technologies.

 

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Adrian Lim

Meng-Xing Tang

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Article published online:
06 August 2025