Recent advances in ultrasound-controlled fluorescence technology for deep tissue optical imaging

Abstract

Fluorescence imaging is a noninvasive and dynamic real-time imaging technique; however, it exhibits poor spatial resolution in centimeter-deep tissues because biological tissues are highly scattering media for optical radiation. The recently developed ultrasound-controlled fluorescence (UCF) imaging is a novel imaging technique that can overcome this bottleneck. Previous studies suggest that the effective contrast agent and sensitive imaging system are the two pivotal factors for generating high-resolution UCF images ex vivo and/or in vivo. Here, this review highlights the recent advances (2015-2020) in the design and synthesis of contrast agents and the improvement of imaging systems to realize high-resolution UCF imaging of deep tissues. The imaging performances of various UCF systems, including the signal-to-noise ratio, imaging resolution, and imaging depth, are specifically discussed. In addition, the challenges and prospects are highlighted. With continuously increasing research interest in this field and emerging multidisciplinary applications, UCF imaging with higher spatial resolution and larger imaging depth may be developed shortly, which is expected to have a far-reaching impact on disease surveillance and/or therapy.

Keywords: Deep tissue; High-resolution; Molecular diagnosis; Temperature-sensitive NIR probes; Ultrasound-controlled fluorescence imaging.

Graphical abstract

Fig. 1

(A) Schematic illustration of the interaction between light and tissue. (B) The schematic diagram of depth of penetration for the NIR-I/II light. (C) The UCF contrast agent's components. UCF: ultrasound-controlled fluorescence.

Fig. 2

(A) The fluorescence image of the mixed contrast agents via local injection in the tumor (Ex/Em = 808/830 nm). The top-right inset is the photograph of the mouse with a breast tumor. The red square is represented as UCF scan area. (B) A thermal imaging of the mouse. (C–F) 2D-UCF images of different depths at X–Y plane. (G–I) The top, right and front side views of the 3D CT image. (J–L) The top, right and front side views of the 3D UCF image. 2D: two-dimensional; 3D: three-dimensional. (Reprint with permission from Ref. [40].)

Fig. 3

(A–C) The 2D fluorescence images of the mouse at different times after intravenous injection of the mixed contrast agents. The red frame in (C) indicates the UCF scan area. (D–G) 2D-UCF images of the different depths at X–Y plane. (H–J) The top, right and front side views of the 3D CT image. (K–M) The top, right and front side views of the 3D UCF image. (Reprint with permission from Ref. [40].)

Fig. 4

(A) Illustration of the fluorescence lifetime-based UCF imaging system [13]. (B) Schematic diagram of the frequency-domain UCF imaging system with a fluorescence intensity readout [38]. (C) Illustration of ICCD camera-based time-domain UCF imaging system [51]. (D) Schematic of the preparation of NIR-II polymer dots [56]. EMCCD: electron multiplying charge coupled device; ICCD: intensified charge coupled device. (Reprint with permission from Refs. [13,38,51,56].)