Ultrasound-Switchable Fluorescence Imaging in Biological Tissues

Ultrasound‐switchable fluorescence (USF) imaging combines the deep penetration and spatial selectivity of focused ultrasound with the high sensitivity and specificity of fluorescence detection. By applying a tightly focused ultrasound beam, the local environment of tailored contrast agents is transiently modified—typically through a modest temperature rise—triggering a rapid and reversible change in their emission. This on–off switching confines the fluorescent signal to a small, ultrasound‐defined volume, substantially improving spatial resolution in centimetre‐deep tissues compared with conventional diffuse fluorescence imaging. The technique leverages near‐infrared fluorophores embedded in thermoresponsive polymers or phase‐changing nanodroplets, permitting high signal‐to‐noise ratios by suppressing background fluorescence. USF has been demonstrated in tissue phantoms, ex vivo specimens and small‐animal models, revealing potential for molecular‐level sensing, targeted probe delivery and multimodal structural–functional studies. Ongoing advances aim to refine agent stability, tailor thermal thresholds for in vivo safety, accelerate imaging speed and integrate with complementary modalities to enable real‐time, high‐resolution mapping of disease biomarkers and physiological processes deep within living organisms.

Research from Nature Portfolio

Recent studies have addressed key challenges in the design and application of USF contrast agents and imaging hardware. One foundational report improved the chemical stability and shelf life of indocyanine‐green‐loaded polymer nanoparticles, while incorporating functional groups for future molecular targeting and optimising the thermal activation threshold to just above body temperature. A subsequent investigation achieved the first successful in vivo USF imaging in small mammals, demonstrating high‐resolution mapping of tumours and spleen accumulation after both local and intravenous administrations, and validating accuracy through complementary computed tomography. More recently, the development of a time‐domain USF imaging system using an intensified charge‐coupled device camera has revealed detailed trade‐offs between acquisition parameters and image quality, guiding strategies to balance spatial resolution, signal‐to‐noise ratio and temporal throughput for potential clinical translation.

Ultrasound-Switchable Fluorescence Imaging in Biological Tissues publication trend

The graph below shows the total number of articles in ultrasound-switchable fluorescence imaging in biological tissues across all publications each year (not limited to Nature Index journals).

Technical terms

Ultrasound-Switchable Fluorescence (USF): An imaging modality in which focused ultrasound transiently modulates fluorophore emission within a defined focal volume.

Contrast Agent: A tailored fluorescent probe whose optical properties change in response to an external stimulus (e.g., temperature or phase change).

Focused Ultrasound: A convergent acoustic beam that produces localised heating or mechanical effects at a precise target depth.

Signal-to-Noise Ratio (SNR): The ratio of the useful fluorescence signal to background noise, reflecting image clarity and sensitivity.

Near-Infrared (NIR) Fluorophore: A fluorescent molecule absorbing and emitting light in the 650–900 nm range, suited for deep‐tissue penetration.

References

1. High-Resolution Ultrasound-Switchable Fluorescence Imaging in Centimeter-Deep Tissue Phantoms with High Signal-To-Noise Ratio and High Sensitivity via Novel Contrast Agents. PLOS ONE (2016).
2. New generation ICG-based contrast agents for ultrasound-switchable fluorescence imaging. Scientific Reports (2016).
3. In vivo ultrasound-switchable fluorescence imaging. Scientific Reports (2019).
4. An ICCD camera-based time-domain ultrasound-switchable fluorescence imaging system. Scientific Reports (2019).
5. Exploring NIR Aza-BODIPY-Based Polarity Sensitive Probes with ON-and-OFF Fluorescence Switching in Pluronic Nanoparticles. Polymers (2020).
6. Fluorescent Phase-Changing Perfluorocarbon Nanodroplets as Activatable Near-Infrared Probes. International Journal of Molecular Sciences (2022).
7. In vivo ultrasound-switchable fluorescence imaging using a camera-based system.. Biomedical Optics Express (2020).