A Review of Clinical Applications for Super-resolution Ultrasound Localization Microscopy

Microvascular structure and hemodynamics are important indicators for the diagnosis and assessment of many diseases and pathologies. The structural and functional imaging of tissue microvasculature in vivo is a clinically significant objective for the development of many imaging modalities. Contrast-enhanced ultrasound (CEUS) is a popular clinical tool for characterizing tissue microvasculature, due to the moderate cost, wide accessibility, and absence of ionizing radiation of ultrasound. However, in practice, it remains challenging to demonstrate microvasculature using CEUS, due to the resolution limit of conventional ultrasound imaging. In addition, the quantification of tissue perfusion by CEUS remains hindered by high operator-dependency and poor reproducibility. Inspired by super-resolution optical microscopy, super-resolution ultrasound localization microscopy (ULM) was recently developed. ULM uses the same ultrasound contrast agent (i.e. microbubbles) in CEUS. However, different from CEUS, ULM uses the location of the microbubbles to construct images, instead of using the backscattering intensity of microbubbles. Hence, ULM overcomes the classic compromise between imaging resolution and penetration, allowing for the visualization of capillary-scale microvasculature deep within tissues. To date, many in vivo ULM results have been reported, including both animal (kidney, brain, spinal cord, xenografted tumor, and ear) and human studies (prostate, tibialis anterior muscle, and breast cancer tumors). Furthermore, a variety of useful biomarkers have been derived from using ULM for different preclinical and clinical applications. Due to the high spatial resolution and accurate blood flow speed estimation (approximately 1 mm/s to several cm/s), ULM presents as an enticing alternative to CEUS for characterizing tissue microvasculature in vivo. This review summarizes the principles and present applications of CEUS and ULM, and discusses areas where ULM can potentially provide a better alternative to CEUS in clinical practice and areas where ULM may not be a better alternative. The objective of the study is to provide clinicians with an up-to-date review of ULM technology, and a practical guide for implementing ULM in clinical research and practice.