Three-Dimensional Deep-Tissue Functional and Molecular Imaging by Integrated Photoacoustic, Ultrasound, and Angiographic Tomography (PAUSAT)

Abstract

Non-invasive small-animal imaging technologies, such as optical imaging, magnetic resonance imaging and x-ray computed tomography, have enabled researchers to study normal biological phenomena or disease progression in their native conditions. However, existing smallanimal imaging technologies often lack either the penetration capability for interrogating deep tissues (e.g., optical microscopy), or the functional and molecular sensitivity for tracking specific activities (e.g., magnetic resonance imaging). To achieve functional and molecular imaging in deep tissues, we have developed an integrated photoacoustic, ultrasound and angiographic tomography (PAUSAT) system by seamlessly combining light and ultrasound in a non-invasive manner. PAUSAT can perform three imaging functions simultaneously with complementary contrast: high-frequency B-mode ultrasound imaging of tissue morphology, microbubbleenabled acoustic angiography of vasculature, and multi-spectral photoacoustic imaging of molecular probes. PAUSAT can provide three-dimensional (3D) multi-contrast images that are automatically co-registered, with high spatial resolutions at large depth. Using PAUSAT, we conducted proof-of-concept in vivo experiments on various small animal models: monitoring longitudinal development of placenta and embryo during mouse pregnancy, tracking biodistribution and metabolism of near-infrared organic dye on the whole-body scale, and detecting genetically-encoded breast tumor expressing photoswitchable phytochromes. These results have collectively demonstrated that PAUSAT has broad applicability in biomedical research, providing comprehensive structural, functional, and molecular imaging of small animal models.

Multiscale photoacoustic tomography using reversibly switchable thermochromics

“…2(c) ], experiments were performed using a hybrid imaging system for PACT and high-frequency ultrasound imaging. 40 – 42 The excitation source was a 532-nm pulse laser (Q-smart 850, Quantel Laser, MT, USA), and the PRR was 10 Hz. The excitation light was coupled into a two-branch linear fiber bundle that flanked the linear transducer array and guided to the target surface.…”

“…The absorption spectra of ReST vary with changes in temperature, 33 – 35 leading to changes in photoacoustic intensity. The probes were imaged using three implementations of PAT: (1) second-generation optical-resolution photoacoustic microscopy (SG-OR-PAM), 36 – 38 which images ReST at submillimeter depth and micrometer level resolution; (2) high-speed wide-field photoacoustic microscopy using a cylindrically focused transparent ultrasound transducer (CFT-UT-PAM), 39 which monitors thermal changes in real time; and (3) photoacoustic computed tomography (PACT) with a linear transducer array, 40 – 42 which provides imaging with large penetration depth and a spatial resolution of hundreds of micrometers in vitro and in vivo . The results show that ReST exhibit excellent properties for photoacoustic imaging and are promising new contrast agents that improve image quality in photoacoustic molecular imaging.…”

“…(2) high-speed wide-field photoacoustic microscopy using a cylindrically focused transparent ultrasound transducer (CFT-UT-PAM), 39 which monitors thermal changes in real time; and (3) photoacoustic computed tomography (PACT) with a linear transducer array, [40][41][42] which provides imaging with large penetration depth and a spatial resolution of hundreds of micrometers in vitro and in vivo. The results show that ReST exhibit excellent properties for photoacoustic imaging and are promising new contrast agents that improve image quality in photoacoustic molecular imaging.…”

Nanoscale Contrast Agents for Ultrasound Imaging of Musculoskeletal System

“…Only BR55 [ 52 ] is currently in preclinical trials and the application of nanocarriers still lacks large sample studies to assess biosafety and reliable biocompatibility. Many nUCAs under study are primed for bimodal or even multimodal imaging and combination with modalities such as fluorescence imaging and PAI can help enhance the contrast and resolution of in vivo imaging [ 53 , 54 ]; however, the expected imaging and therapeutic functions of multimodal contrast agents in the human body are yet to be realized. Therefore, exploring and refining the new ultrasonic nanotechnology and studying its biosafety issues will accelerate the translation of some nUCAs for clinical applications.…”

Photoacoustic-enabled automatic vascular navigation: accurate and naked-eye real-time visualization of deep-seated vessels

“…21,22 However, Doppler ultrasound has a low sensitivity for imaging small vessels. 23 Photoacoustic imaging (PAI) [24][25][26][27][28] utilizes the specific absorption properties of hemoglobin to achieve direct imaging of blood vessels with high sensitivity and deep penetration. Noninvasive imaging of blood vessels can be performed by PAI to provide high-resolution vascular imaging for preoperative planning.…”