Super-resolution contrast-enhanced ultrasound: recent advances

Super-resolution CEUS: recent advances

Article information

Ultrasonography. 2026;45(3):218-231

Publication date (electronic) : 2026 March 2

doi : https://doi.org/10.14366/usg.25238

Yunlin Huang ¹

, Rui Cheng ¹

, Ying Wang ¹

, Yi Dong^,¹

, Jeong Min Lee^,²

¹Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

²Department of Radiology, Seoul National University Hospital, Seoul, Korea

Correspondence to: Yi Dong, MD, PhD, Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China Tel. +86-21-25077258 Fax. +86-21-25077258 E-mail: drdaisydong@hotmail.com

Jeong Min Lee, MD, Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel. +82-2-2072-3154 Fax. +82-2-743-6385 E-mail: jmsh@snu.ac.kr

Received 2025 November 16; Revised 2026 January 13; Accepted 2026 March 2.

Abstract

Super-resolution (SR) contrast-enhanced ultrasound (CEUS) is a novel sub-diffraction imaging modality that surpasses the diffraction limitations of conventional ultrasound and enables visualization of intricate microvascular architectures. SR CEUS provides improved quantification of hemodynamics and enhanced visualization of microvessels, thereby overcoming several inherent limitations of traditional CEUS. Initially demonstrated for imaging microvessels in the brains of small animals, SR CEUS has subsequently been investigated in multiple fields, including oncology, nephrology, and neurological research, with applications reported in breast cancer, chronic liver disease, and lymph node evaluation. However, clinical translation remains limited by prolonged acquisition times resulting from suboptimal microbubble detectability and the requirement for diluted contrast agents. This review summarizes the technical principles, clinical applications, current limitations, and future directions of SR CEUS from a clinical perspective.

Keywords: Super-resolution contrast-enhanced ultrasound; Ultrasound localization microscopy; Microbubbles; Visualization; Microvessels; Hemodynamics

Introduction

Contrast-enhanced ultrasound (CEUS) is widely used to differentiate malignant from benign lesions because it enables real-time visualization of vascular organ perfusion [1–5]. Through time-intensity curve analysis, dynamic CEUS can provide objective quantitative parameters that are not accessible through routine visual assessment alone [6–9]. However, CEUS cannot resolve microvasculature smaller than the acoustic wavelength [4,10–12]. Super-resolution (SR) CEUS, also referred to as ultrasound localization microscopy (ULM), represents a paradigm shift in microvascular imaging and was inspired by developments in optical SR microscopy [13–15].

SR CEUS has potential applications across multiple vascular-rich organ systems and is distinguished by its independence from the Doppler angle, thereby expanding the spectrum of clinical applications of CEUS. By exploiting rapid, short-duration (~3-second) fluctuations in contrast agent distribution, SR CEUS enhances the visualization of microvascular structures during organ imaging. It improves the spatial resolution of CEUS by approximately tenfold while preserving comparable imaging penetration [10,16,17]. The transition from conventional intensity-based CEUS, which is limited in capillary resolution because of spatial constraints, to localization-based SR CEUS enables tracking of individual microbubbles and reveals microcirculatory architectures that were previously undetectable.

This review aims to introduce the principles of SR CEUS, describe its clinical significance, and discuss current challenges and future perspectives.

Technical Principles of SR CEUS

Microbubble Tracking

The fundamental principle of SR CEUS is derived from ULM, which relies on the accurate localization and tracking of individual microbubbles within the circulatory system rather than on the backscattered echoes used to generate conventional ultrasound images [18,19]. This approach achieves a resolution as fine as 10 μm and enables visualization of capillaries and assessment of their perfusion. Notably, it does so without compromising penetration depth or signal-to-noise ratio [10]. ULM surpasses the diffraction limit of conventional ultrasound (~150 μm) by tracking the spatiotemporal movement of microbubbles [20–22]. Key steps include motion correction to reduce respiratory and cardiac artifacts, spatial isolation to separate overlapping microbubble signals, centroid localization for sub-wavelength accuracy, and trajectory reconstruction. Collectively, these steps generate capillary-scale microvascular maps (~10 μm resolution) and permit direct measurement of blood flow velocity and direction [22].

SR CEUS involves the acquisition of ultrasound acoustic data, detection of scattering signals produced by microbubbles, and separation of those signals by rejecting overlapping echoes. The positions of the microbubbles are determined by calculating the centroids of their point spread functions and tracking them across sequential frames to map microvessels and analyze velocity profiles [23]. SR CEUS can achieve high-resolution imaging at 500 frames per second, enabling the generation of three distinct imaging maps: vascular density, flow velocity, and velocity direction.

Role of High-Frame-Rate Imaging and Plane-Wave Ultrasound

Conventional ultrasound systems generally operate at relatively low frame rates, typically not exceeding 50 Hz, and therefore lack the temporal resolution required to track rapidly moving microbubbles effectively [23,24]. This limitation can be mitigated by plane-wave imaging, which uses unfocused waves to cover the entire field of view with a single pulse [16,25,26]. As a result, substantially higher frame rates can be achieved, ranging from 1–5 kHz on clinical scanners to more than 20 kHz on research systems, far exceeding those of traditional line-by-line scanning methods.

The ultrahigh speed of plane-wave imaging captures the displacement of individual microbubbles between successive frames, thereby minimizing motion blur and permitting precise velocity measurements across a wide range, from 1 mm/s to several centimeters per second. When integrated with high-frame-rate CEUS, this approach enables accurate localization and tracking of microbubbles. It also facilitates the generation of detailed maps of microbubble density and velocity, which form the basis of SR CEUS [25]. To support the reliable detection, separation, and tracking of these rapidly moving microbubbles, most SR CEUS implementations employ high-frame-rate plane-wave imaging [25,27]. Innovations such as motion-model ULM have adapted the technique for standard clinical scanners with lower frame rates, thus improving its translational potential [16].

Deep Learning in Enhancing SR CEUS

More recently, deep learning has played an increasingly important role in improving both the resolution and processing efficiency of SR CEUS [16,26,28–32]. Conventional SR CEUS methods typically require manual calibration to distinguish microbubble signals from tissue clutter, a process that is both time-consuming and sensitive to noise. Deep learning approaches streamline this process by using algorithms such as convolutional neural networks to detect microbubble signatures directly from raw ultrasound data [28,30,33]. These approaches suppress background noise, correct localization errors (including trajectory interruptions caused by motion artifacts), and substantially accelerate the processing of large datasets [33].

In a previous study, an artificial intelligence model developed by van Sloun et al. [33] increased the signal-to-noise ratio of microbubble detection by 40% while reducing processing time by 90%. Generative adversarial networks have also been used to predict microbubble trajectories, compensating for tracking limitations in low-frame-rate systems and enabling near-real-time three-dimensional (3D) microvascular reconstruction in clinical settings. Together, these techniques may help mitigate the substantial computational burden of SR CEUS [34].

Clinical Applications of SR CEUS

SR CEUS has substantial clinical significance, especially in microcirculation imaging, where it offers an unmatched ability to visualize tissue microvascular structure and perfusion heterogeneity noninvasively and in vivo. These capabilities are valuable for evaluating tumor biology, monitoring treatment response, and predicting prognosis [10,35]. SR CEUS acquisitions are typically performed using specialized ultrafast ultrasound scanners capable of plane-wave imaging, such as the Resona A20 (Mindray, Shenzhen, China), EPIQ 7 Elite (Philips, Cambridge, MA, USA) [36–38], and ULTIMUS 9E (VINNO Technology Co. Ltd., Suzhou, China). SR CEUS processing is generally performed offline using software such as MATLAB (MathWorks, Natick, MA, USA) [39–42]. Initially demonstrated in small-animal brain imaging, SR CEUS has since been investigated in oncology, nephrology, and neurology, including studies of breast cancer, liver disease, and lymph nodes (Table 1) [18,36–49].

Table 1.

SR CEUS findings in various organs in clinical research

SR CEUS in Oncology Applications

SR CEUS and habitat imaging

Habitat imaging is a novel image analysis technique that noninvasively captures spatial heterogeneity within tumors. It works by partitioning heterogeneous tissues, such as tumors, into distinct subregions with different functional or phenotypic characteristics [50]. Over the past decade, perfusion habitat imaging has been performed predominantly using magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET), with MRI being the most widely used modality [51–54]. Compared with these established modalities for characterizing tumor heterogeneity, SR CEUS enables high-resolution multiparametric imaging of microvascular networks at the micron scale and generates functional maps of vessel density, blood flow velocity, and flow direction [32]. Building on these capabilities, habitat imaging can perform spatial clustering and analysis of these parameters to identify clinically meaningful subregions, such as highly perfused hypoxic zones or low-flow disorganized vascular areas [10]. This integrated approach improves the precision and interpretability of tumor heterogeneity analysis.

Focal liver lesions

In oncology, several SR CEUS parameters, including vessel density, local flow direction entropy, and fractal dimension, have shown utility in distinguishing malignant from benign liver lesions [43]. In a recent retrospective study, SR CEUS was used to assess microvascularization in hepatic lesions, with vascular density and vessel diameter quantified using structure-based lines and statistically compared across groups (malignant, benign, post-intervention, and Morbus Osler) [37]. The results showed significant differences between benign lesions and both surrounding capillary regions (P<0.001) and healthy liver tissue (P<0.01). The malignant and Morbus Osler groups had higher vascular measurements, although these differences were not significant. Image quality declined with increasing tissue depth. Focal nodular hyperplasia displayed higher vascular density than hemangioma, whereas cysts often lacked detectable microvascular signals [37]. Furthermore, SR CEUS can detect early microvascular changes in hepatocellular carcinoma after transarterial chemoembolization, with high concordance with MRI and histological findings [55]. SR CEUS enables quantitative assessment of microvascularization within hepatic lesions and aids in differentiating benign from malignant vascular patterns (Fig. 1). It also shows promise for monitoring therapeutic response after treatment. Its capacity to visualize capillary-level vascular detail offers a useful complement to traditional imaging methods.

Fig. 1.

Contrast-enhanced ultrasound (CEUS) image and super-resolution (SR) ultrasound imaging maps from a 39-year-old man with glycogen storage disease type Ia and hepatocellular adenoma.

A. The arterial phase of CEUS shows enhancement of the focal liver lesion 12 seconds after contrast agent administration. B–D. SR CEUS images provide detailed maps of vascular density (B), velocity direction (C), and flow velocity (D). CEUS examination and SR CEUS analysis were performed using the Resona A20 ultrasound system (Mindray, Shenzhen, China) equipped with an SC7-1U probe (1–7 MHz).

Breast lesions

For breast lesions, SR CEUS shows considerable potential for supporting differential diagnosis, with microvessel density serving as a key imaging marker [25,44]. A clinical trial is currently underway to evaluate the effectiveness of SR CEUS in distinguishing benign from malignant breast tumors and in correlating SR CEUS metrics with histopathological biomarkers [45]. In prior research to optimize an SR CEUS protocol for patients with breast cancer, SR CEUS images were generated offline through motion correction, microbubble detection, localization, and tracking. Higher microbubble doses and faster injection rates yielded the greatest numbers of detected microbubbles, tracks, and vessel coverage, thereby providing the most detailed vascular maps without significant signal overlap. The acquisition window was limited to 3.5 minutes because of motion-related constraints. In addition, vessel coverage derived from SR CEUS was comparable to the histological vessel fraction and displayed a significant correlation with mean tumor elasticity [46]. Representative SR CEUS images from a patient with breast cancer are shown in Fig. 2. Notably, SR CEUS has also demonstrated a marked reduction in the internal microvascular architecture of breast cancer after treatment with a vascular-disrupting agent [56,57]. These findings suggest potential utility for the early identification of breast tumor response to vascular-disrupting agent therapy.

Fig. 2.

Contrast-enhanced ultrasound (CEUS) image and super-resolution (SR) ultrasound imaging maps from a 30-year-old woman with intraductal papilloma of the breast.

A. The arterial phase of CEUS demonstrates enhancement of the breast lesion 19 seconds after contrast agent administration. B–D. SR CEUS images provide detailed maps of vascular density (B), flow velocity (C), and flow velocity direction (D). CEUS examination and SR CEUS analysis were performed using the Resona A20 ultrasound system (Mindray, Shenzhen, China) equipped with an SC7-1U probe (1–7 MHz).

Lymph nodes

Alterations in lymph node microcirculation may indicate cancer metastasis [58]. SR CEUS has revealed irregular local flow patterns in lymph nodes, thus helping differentiate metastases from benign lymph node conditions [36,41,59]. In a pilot study, 54 patients with enlarged superficial lymph nodes were prospectively enrolled and underwent SR CEUS. Quantitative parameters were assessed using a protocol that included 0.5 mL of contrast agent and a 6-second acquisition time. The results showed that microvascular density, flow-weighted vessel density, perfusion index, and velocity variance were useful imaging biomarkers for clinical evaluation [36]. Representative SR CEUS images from a patient with lymphoma are shown in Fig. 3.

Fig. 3.

3. Contrast-enhanced ultrasound (CEUS) image and super-resolution (SR) ultrasound imaging maps from a 46-year-old man with lymphoma.

A. The arterial phase of CEUS shows enhancement of the left axillary lymph node 10 seconds after contrast agent injection. B–D. SR CEUS images provide maps of vascular density (B), flow velocity (C), and velocity direction (D). CEUS examination and SR CEUS analysis were performed using the ULTIMUS 9E ultrasound system (VINNO Technology Co. Ltd, Suzhou, China) equipped with an S1-8C probe (1.5–7 MHz).

Thyroid nodules

SR CEUS has also been applied to thyroid nodules. This technique enables noninvasive quantification of microvascular density and flow rate within nodules. In addition, it provides a detailed visualization of microvasculature beyond the capabilities of conventional Doppler ultrasound or CEUS, thereby offering promising imaging biomarkers for differentiating benign from malignant lesions [39]. Representative SR CEUS images from a patient with papillary thyroid carcinoma are shown in Fig. 4.

Fig. 4.

Contrast-enhanced ultrasound (CEUS) image and super-resolution (SR) ultrasound imaging maps from a 37-year-old patient with papillary thyroid carcinoma in the right lobe.

A. After contrast agent administration, the thyroid nodule exhibits hypoenhancement throughout the CEUS examination. B–D. SR CEUS images provide maps of vascular density (B), flow velocity (C), and flow direction (D). CEUS examination and SR CEUS analysis were performed using the Resona A20 ultrasound system (Mindray, Shenzhen, China) equipped with an SC7-1U probe (1–7 MHz).

Prostate cancer

For neoplasms of the genitourinary system, SR CEUS appears valuable for identifying imaging biomarkers and facilitating the differential diagnosis of prostate lesions. Butler et al. [40] developed and validated SR ultrasound imaging algorithms for mapping prostate microvasculature using CEUS data. In clinical data from 14 patients, SR CEUS identified regions with high flow velocity and volume in Gleason 7 cancers, along with avascular areas, whereas cancer-free regions displayed consistently low flow. Furthermore, Huang et al. [42] applied SR CEUS to 127 patients with prostate lesions and quantified microvascular features; malignant lesions showed significantly higher microvessel density, diameter, velocity, tortuosity, and fractal number than benign lesions. These studies demonstrate that SR CEUS can noninvasively depict detailed microvascular patterns in prostate cancer, including increased vessel density, elevated flow velocity, greater structural complexity in malignant regions, and the presence of avascular zones.

Testicular lesions

For testicular lesions, a retrospective study analyzed 31 patients who underwent conventional ultrasound, color Doppler ultrasound, and CEUS, with two SR post-processing techniques applied. The findings demonstrated that SR CEUS enhances visualization of microvascular structures and perfusion characteristics in testicular lesions, thereby facilitating differential diagnosis and potentially reducing unnecessary surgical interventions [60].

SR CEUS in Non-oncology Applications

Kidney

In addition to its oncologic applications, SR CEUS may also be useful in non-oncologic settings. SR CEUS density and velocity images reveal detailed vascular structures and complex hemodynamics within the renal cortex [25,61]. Renal capillaries, which deliver oxygen and nutrients to the tubules, are essential for the early detection of kidney allograft dysfunction. SR CEUS can concurrently assess microcirculatory alterations across different functional regions of the kidney, especially in the medulla, which is difficult to evaluate using conventional techniques [62]. In a pilot study, 16 kidney transplant recipients were enrolled to evaluate SR ultrasound imaging for visualizing microvasculature and quantifying microvessel density and microvascular flow rate, as well as CEUS for deriving time-intensity-curve parameters. The study showed that SR ultrasound imaging can depict renal allograft microvasculature and that microvessel density combined with time to peak serves as a useful noninvasive marker for assessing graft dysfunction [47]. Representative SR CEUS images of a healthy kidney are shown in Fig. 5.

Fig. 5.

Contrast-enhanced ultrasound (CEUS) image and super-resolution (SR) ultrasound imaging maps of a healthy kidney in a 9-year-old boy.

A. The arterial phase of CEUS shows enhancement of the renal cortex 16 seconds after contrast agent administration. B–D. SR CEUS images provide maps of vascular density (B), flow velocity (C), and velocity direction (D). CEUS examination and SR CEUS analysis were performed using the Resona A20 ultrasound system (Mindray, Shenzhen, China) equipped with an SC7-1U probe (1–7 MHz).

Liver

SR CEUS has demonstrated strong capability for visualizing the microvasculature of both healthy and diseased human livers, including cases of acute-on-chronic liver failure, with markedly improved spatial resolution when high-frame-rate clinical ultrasound scanners are used and acquisition times are brief (less than 10 seconds) [25]. SR CEUS provides angle-independent velocity mapping across a broad range (1–60 mm/s), highlighting its potential for noninvasive evaluation of hepatic microvascular pathology in clinical settings [25]. In addition, the noninvasive evaluation of portal venous pressure in patients with portal hypertension remains a key focus of clinical research, for which SR CEUS shows considerable potential. A previous study introduced a vessel-labeling SR ultrasound technique designed for targeted perfusion imaging of the hepatic portal vein and its downstream vasculature. This method was validated in healthy mice and improves spatial resolution when combined with SR ultrasound while enabling noninvasive perfusion evaluation based on arrival time distribution maps [37]. Similar results were reported by Yang et al. [63], who investigated SR CEUS combined with vessel-labeling ultrasound for portal venous perfusion imaging in mice. Further studies and validation in humans are required to confirm the clinical utility of SR CEUS, which may ultimately reduce the need for invasive procedures. Representative SR CEUS images of a healthy liver are shown in Fig. 6.

Fig. 6.

Super-resolution (SR) contrast-enhanced ultrasound (CEUS) imaging of a healthy liver in a 28-year-old woman.

A. Conventional grayscale ultrasound shows homogeneous liver parenchyma. B–D. SR CEUS images provide maps of vascular density (B), velocity direction (C), and flow velocity (D). CEUS examination and SR CEUS analysis were performed using the Resona A20 ultrasound system (Mindray, Shenzhen, China) equipped with an SC7-1U probe (1–7 MHz).

Carotid plaque neovascularization

Carotid plaque neovascularization is an important contributor to plaque vulnerability and rupture, together with other pathological features such as calcification and intraplaque hemorrhage. However, visualization and accurate characterization of these microvessels remain challenging with conventional ultrasound or CEUS, primarily due to resolution limits. Leroy et al. [18] quantified plaque vascularization using SR CEUS and compared the results with histological findings. The study showed that SR CEUS effectively distinguished plaques with neovascularization from those without. The median number of microbubbles tracked per second was significantly higher in histologically confirmed neovascularized plaques (group II, 3.55) than in plaques without neovascularization (group I, 0.027; P=0.00049). Hemodynamic parameters derived from SR CEUS, including the number of microbubbles tracked, track length, and velocity, showed strong correlations with histological findings. In contrast, conventional power Doppler signals could not differentiate between the two groups. Compared with conventional CEUS, SR CEUS provided a more precise assessment of neovascularization, demonstrated by a significantly greater number of microbubbles passing during systole than during diastole (P=0.021). In addition, ULM quantified intraplaque flow velocities, revealing a median microbubble velocity of 57 mm/s in patients from group II. These findings suggest that SR CEUS enables high-resolution visualization of plaque neovascularization and may represent a promising noninvasive technique for assessing carotid plaque vulnerability.

Others

SR CEUS has also been reported to visualize the fistula tract in a patient with intestinal Behçet disease [38]. Conventional CT and standard CEUS could not clearly delineate the fistula tract. In contrast, SR CEUS successfully demonstrated a heterogeneous distribution and tortuous course of microvessels within the lesion area, together with vascular interruption at the suspected fistula site, thereby clearly depicting the morphology of the fistula [38]. By enabling micron-scale vascular imaging, SR CEUS introduces a novel noninvasive diagnostic approach for identifying enterovesical fistula in patients with Behçet disease.

SR CEUS in Neurology and Cardiology Applications

Preclinical study

Approximately a decade ago, SR CEUS was demonstrated for noninvasive transcranial imaging of rat cerebral microvasculature with a resolution of 10 μm×8 μm, enabling visualization of capillaries as small as 9 μm and differentiation of vessels separated by only 16 μm [16]. By accumulating more than 75,000 frames, the method successfully reconstructed complex vascular maps and quantified blood flow velocities across a broad dynamic range, from 1 mm/s to several centimeters per second, including directional flow components [16]. Subsequent preclinical studies extended SR CEUS applications to other organs. For example, ultrafast ultrasound imaging has been used to achieve SR imaging of myocardial microvasculature in combination with PET, demonstrating the feasibility of mapping cardiac perfusion at microscopic scales [54].

Cerebrovascular uses

In clinical research, SR CEUS was used to visualize microvascular reorganization in seven neonates with vein of Galen malformation before and after endovascular therapy [48]. The primary observations in SR CEUS images included structural microvascular alterations such as decreased flow velocity, reduced dispersity, and increased tortuosity in gray matter. In addition, a transient velocity increase in white matter suggested microvascular reorganization. Another key finding involved a patient with cerebral infarction, in which SR CEUS distinguished infarcted tissue from healthy tissue. The infarcted region exhibited higher flow velocity, increased dispersity, and reduced tortuosity, indicating microvascular disruption [48]. SR CEUS has also enabled noninvasive high-resolution imaging of microvascular structure and function in neonates, facilitating detailed monitoring of therapeutic outcomes and pathological changes in cerebral perfusion following neurovascular interventions. Furthermore, SR CEUS enables noninvasive high-resolution imaging of cerebral perforating arteries, highlighting its potential for diagnosing microvascular pathologies such as moyamoya disease. Denis et al. [49] used transcranial SR CEUS to image perforating arteries in patients with moyamoya disease and reported that SR CEUS could reconstruct perforating arteries with an average diameter of 0.8±0.3 mm that were not detectable using conventional 3T time-of-flight magnetic resonance angiography or color Doppler ultrasound. In addition, SR CEUS revealed differences in the spatial distribution of vessels between patients with moyamoya disease and control participants (P=0.05), further highlighting its enhanced capability for visualizing perforating arteries [49].

Evidence of Added Clinical Value over Conventional CEUS

SR CEUS enables quantification of neovascularization and assessment of microvascular alterations, whereas conventional CEUS has not focused primarily on the analysis of vascular patterns and vessel density. By addressing this important limitation of conventional CEUS, SR CEUS shifts diagnostic assessment from subjective interpretation of enhancement patterns and kinetics toward objective measurement of microvascular morphology and density. Accordingly, SR CEUS complements and extends the current range of quantitative CEUS tools by introducing a new dimension of microvascular morphology rather than simply providing an alternative hemodynamic curve. For example, in small hepatocellular carcinoma foci measuring ≤10 mm in diameter, the washout sign on which conventional CEUS relies may be faint or entirely absent, thereby complicating diagnosis. In such cases, SR CEUS may provide an additional diagnostic criterion, namely the extent of irregular neovascularization [37]. In renal transplantation, SR CEUS visualized the microvasculature at significantly higher resolution than color Doppler flow imaging and conventional CEUS, including visualization of submillimeter vessels [47]. These findings indicate that SR CEUS may provide supplementary and potentially more reliable diagnostic information than conventional CEUS alone for detecting small lesions.

Current Challenges and Future Perspectives

SR CEUS has several current limitations and practical challenges. First, performing SR CEUS with a freehand transducer can be difficult, particularly in organs such as the kidney and liver, where tissue motion caused by respiration is substantial and difficult to control [31,64]. Although asking patients to hold their breath may reduce motion, it is impractical to expect this throughout the entire imaging acquisition. CEUS image acquisition is also time-consuming, often requiring several minutes to localize thousands of microbubbles and generate an SR ultrasound image [15,26,65]. High microbubble concentrations can produce overlapping signals, necessitating diluted contrast agent doses that may prolong acquisition time and reduce signal intensity [19,20]. In addition, a single imaging session captures only one cross-sectional tissue or tumor slice, making it difficult to comprehensively evaluate tissue or tumor heterogeneity. Two-dimensional (2D) SR CEUS is further limited by out-of-plane motion artifacts and reduced elevational resolution [21,59,66,67]. Moreover, SR CEUS currently requires ultrafast ultrasound equipment and time-intensive data processing, neither of which is yet widely available, and no standardized imaging protocols or quantitative criteria have been established across centers. Finally, SR CEUS remains constrained by the physical limitations of ultrasound, particularly penetration depth. Marked ultrasound attenuation can degrade image quality, especially for lesions deep within the liver parenchyma, in patients with severe hepatic steatosis, or in those with high body mass index. These factors may reduce the number of detectable microbubbles and compromise SR reconstruction, limiting the applicability of the technique in such patients.

Future work should focus on addressing these limitations. Combining SR CEUS with B-mode ultrasound and elastography may enable a more comprehensive assessment of tissue heterogeneity. As SR ultrasound-based habitat imaging evolves, research should prioritize standardization of imaging protocols, validation of SR ultrasound biomarkers in large patient cohorts, and integration of these techniques into routine clinical workflows to support personalized medicine. Although 3D SR CEUS offers a potential solution to the limitations of 2D imaging by providing super-resolved volumetric imaging in all three spatial dimensions [21,59,66,67], it remains largely in the preclinical stage and has not yet been routinely applied in human clinical practice [59,66–69]. Safety considerations related to 3D SR CEUS should also be emphasized; for example, a higher mechanical index (≥0.78) may disrupt the blood-brain barrier during transcranial procedures [70]. With continued technological advances and optimization of processing algorithms, 3D SR CEUS is expected to gradually transition toward clinical application.

Conclusion

SR CEUS represents a major advance in microvascular imaging and has substantial translational potential in oncology and other clinical fields. Overcoming conventional resolution limits, it enables visualization of microvascular structures and flow that were previously unresolvable. Early clinical studies in oncology, neurology, and nephrology have demonstrated its feasibility and potential value for improving diagnosis and treatment monitoring. Although additional research is needed to address current limitations, ongoing technological advances are expected to support the integration of SR CEUS into routine clinical practice. In the coming years, SR CEUS is expected to emerge as an important adjunct to conventional ultrasound, enhancing diagnostic precision and providing new quantitative biomarkers of disease.

Notes

Author Contributions

Conceptualization: Dong Y, Lee JM. Data acquisition: Huang Y. Data analysis or interpretation: Cheng R, Wang Y. Drafting of the manuscript: Huang Y, Cheng R, Wang Y. Critical revision of the manuscript: Dong Y, Lee JM. Approval of the final version of the manuscript: all authors.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Acknowledgments

This study was supported by the Sino-German Mobility Program of the National Natural Science Foundation of China (NSFC) and the Deutsche Forschungsgemeinschaft (DFG) (Grant No. M-0504), as well as the NSFC (Grant No. 82071942).

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Notes

Key points

Super-resolution (SR) contrast-enhanced ultrasound (CEUS) represents a major advance in microvascular imaging, enabling visualization of vascular structures and flow previously deemed unresolvable. Its translational potential is supported by preliminary feasibility studies in oncology, neurology, and nephrology, which suggest improved opportunities for diagnosis and treatment. As technological advances continue, SR CEUS is expected to become an important clinical adjunct that enhances diagnostic accuracy and provides novel quantitative biomarkers.

Organ	Type of disease	No. of patients or lesions	SR CEUS parameters	SR CEUS findings	Study
Liver	Focal lesions	46 Benign, 8 malignant, 5 post intervention, 6 Morbus Osler	Capillary density and vessel diameter measured in four ROIs: hilar vessels, lesion (center-to-edge), normal parenchyma, and subcapsular vascular region	Significant differences in capillary density measurements between benign lesions and reference regions (capillary bed, normal liver)	Kaiser et al. (2025) [37]
				FNH had significantly higher values of vascular density than those in hemangioma
				Malignant lesions display an extent of irregular neovascularization, while benign liver lesions show regular vascular patterns
				A pronounced degree of neovascularization or vascular changes could be seen in both malignant lesions and Morbus Osler
Liver	Focal lesions	30 HCCs, 11 metastases, 6 FNH	Quantitative parameters: vessel density, flow velocity (min/mean/max), perfusion index, fractal dimension, local flow direction entropy	Significant differences in qualitative patterns among HCC (irregular/eccentric), metastases (peripheral/low-speed), and FNH (uniform/centrifugal/high-speed)	Zeng et al. (2024) [43]
			Qualitative pattern: distribution, velocity, and direction patterns	FNH showed significantly higher vessel density, fractal dimension, and local flow direction entropy than HCC and metastases
				Metastases exhibited a lower perfusion index (especially in the central area) and a lower min flow velocity compared to HCC and FNH
Gastrointestinal	Inflammatory bowel disease	A case of intestinal Behçet's disease with enterovesical fistula	Vascular distribution, tortuosity, and course interruption	Abundant and tortuous microvasculature within the inflamed intestinal wall	Aihemaiti et al. (2025) [38]
Gastrointestinal	Inflammatory bowel disease		Vascular distribution, tortuosity, and course interruption	An interruption in the vascular course at the suspected fistula site	Aihemaiti et al. (2025) [38]
Breast	Breast lesions	20 Benign, 26 malignant	MVD, MFR	MVD derived had the highest correlation with malignancy	Zhang et al. (2022) [44]
Breast	Breast lesions	14 Benign, 17 malignant	Microvascular morphology, MVD, diameter (mean/max), tortuosity (mean/max), flow velocity (mean/max)	Benign lesions showed dot/line/branch-like patterns and higher mean flow velocity	Li et al. (2025) [45]
Breast	Breast lesions	14 Benign, 17 malignant		Malignant lesions showed chaotic patterns and had significantly higher MVD, diameter (mean and max), and max tortuosity	Li et al. (2025) [45]
Breast	Breast cancers	11 Malignant	Vessel coverage maps	Vessel coverage was comparable to the histological vessel fraction	Porte et al. (2024) [46]
Breast	Breast cancers	11 Malignant	Vessel coverage maps	Vessel coverage showed a significant positive correlation with mean tumor elasticity	Porte et al. (2024) [46]
Lymphatic system	Lymph nodes	20 Benign, 34 malignant	MVD, flow-weighted vessel density, perfusion index, fractal dimension, velocity variance, and mean velocity	Benign lymph nodes showed significantly higher MVD, flow-weighted vessel density, perfusion index, and lower velocity variance	He et al. (2025) [36]
Lymphatic system	Lymph nodes	20 Benign, 34 malignant		Malignant lymph nodes showed sparser microvessels, lower perfusion, and greater flow heterogeneity	He et al. (2025) [36]
Lymphatic system	Lymph nodes	4 Benign, 10 malignant	MVD, fractal dimension, mean speed, and local flow direction irregularity	Local flow direction irregularity was significantly higher (by 60%) in metastatic lymph nodes compared to reactive lymph nodes	Zhu et al. (2022) [41]
Lymphatic system	Lymph nodes	4 Benign, 10 malignant		More chaotic micro-flow in malignancy	Zhu et al. (2022) [41]
Thyroid	Thyroid nodules	12 Benign nodules, 12 papillary thyroid carcinoma	MVD and MFR	Both MVD and MFR were significantly higher in benign nodules	Zhang et al. (2022) [39]
				Benign MVD: 0.78 vs. Malignant: 0.59
				Benign MFR: 16.76 mm/s vs. Malignant: 9.86 mm/s
Prostate	Prostate cancers	9 Benign lesions, 5 cancers	Track number, velocity, blood flow	Heterogeneous and complex patterns (high density, high velocity, avascular domains) associated with prostate cancers	Butler et al. (2025) [40]
Prostate	Prostate cancers	78 Benign lesions, 49 cancers	MVD, diameter, velocity, tortuosity, and fractal number	MVD, diameter, velocity, tortuosity, and fractal number were significantly higher in malignant	Huang et al. (2025) [42]
Kidney	Allograft dysfunction	16 Patients with kidney transplants	MVD and MFR	Normal allografts had significantly higher MVD and MFR than dysfunctional allografts	Hu et al. (2024) [47]
Kidney	Allograft dysfunction	16 Patients with kidney transplants	MVD and MFR	MVD was an independent risk factor for allograft dysfunction	Hu et al. (2024) [47]
Vascular	Carotid plaque	8 Plaques without and 18 plaques with neovascularization	Microbubbles count, track length, and velocity	Microbubbles count/s and track length significantly differed between plaques with vs. without neovascularization	Leroy et al. (2025) [18]
Vascular	Carotid plaque	8 Plaques without and 18 plaques with neovascularization	Microbubbles count, track length, and velocity	Microbubbles flow within neovessels was significantly higher during systole than during diastole	Leroy et al. (2025) [18]
Central nervous system	Neonatal brain	7 Pediatric patients with Vein of Galen malformation	Flow velocity, dispersity, tortuosity, distance metric	SR CEUS revealed activation of corticomedullary connections and bridging veins after therapy	Schwarz et al. (2025) [48]
Central nervous system	Neonatal brain	7 Pediatric patients with Vein of Galen malformation	Flow velocity, dispersity, tortuosity, distance metric	Velocity, dispersity, and tortuosity significantly differed between infarcted and viable tissue	Schwarz et al. (2025) [48]
Central nervous system	Adult brain	9 Moyamoya disease	Localizations, tracks, number of perforators, mean spatial distribution distance of tracks, and vessel diameter	Significantly higher MVD in the middle cerebral artery region	Denis et al. (2025) [49]
Central nervous system	Adult brain	9 Moyamoya disease		A more concentrated spatial distribution of tracks	Denis et al. (2025) [49]