On the Importance of Low-Frequency Signals in Functional and Molecular Photoacoustic Computed Tomography.

In photoacoustic computed tomography (PACT) with short-pulsed laser excitation, wideband acoustic signals are generated in biological tissues with frequencies related to the effective shapes and sizes of the optically absorbing targets. Low-frequency photoacoustic signal components correspond to slowly varying spatial features and are often omitted during imaging due to the limited detection bandwidth of the ultrasound transducer, or during image reconstruction as undesired background that degrades image contrast. Here we demonstrate that low-frequency photoacoustic signals, in fact, contain functional and molecular information, and can be used to enhance structural visibility, improve quantitative accuracy, and reduce spare-sampling artifacts. We provide an in-depth theoretical analysis of low-frequency signals in PACT, and experimentally evaluate their impact on several representative PACT applications, such as mapping temperature in photothermal treatment, measuring blood oxygenation in a hypoxia challenge, and detecting photoswitchable molecular probes in deep organs. Our results strongly suggest that low-frequency signals are important for functional and molecular PACT.

On the importance of low-frequency signals in functional and molecular photoacoustic computed tomography.

In photoacoustic computed tomography (PACT) with short-pulsed laser excitation, wideband acoustic signals are generated in biological tissues with frequencies related to the effective shapes and sizes of the optically absorbing targets. Low-frequency photoacoustic signal components correspond to slowly varying spatial features and are often omitted during imaging due to the limited detection bandwidth of the ultrasound transducer, or during image reconstruction as undesired background that degrades image contrast. Here we demonstrate that low-frequency photoacoustic signals, in fact, contain functional and molecular information, and can be used to enhance structural visibility, improve quantitative accuracy, and reduce spare-sampling artifacts. We provide an in-depth theoretical analysis of low-frequency signals in PACT, and experimentally evaluate their impact on several representative PACT applications, such as mapping temperature in photothermal treatment, measuring blood oxygenation in a hypoxia challenge, and detecting photoswitchable molecular probes in deep organs. Our results strongly suggest that low-frequency signals are important for functional and molecular PACT.

Miniaturized Stacked Transducer for Intravascular Sonothrombolysis With Internal-Illumination Photoacoustic Imaging Guidance and Clot Characterization.

Thromboembolism in blood vessels can lead to stroke or heart attack and even sudden death unless brought under control. Sonothrombolysis enhanced by ultrasound contrast agents has shown promising outcome on effective treatment of thromboembolism. Intravascular sonothrombolysis was also reported recently with a potential for effective and safe treatment of deep thrombosis. Despite the promising treatment results, the treatment efficiency for clinical application may not be optimized due to the lack of imaging guidance and clot characterization during the thrombolysis procedure. In this paper, a miniaturized transducer was designed to have an 8-layer PZT-5A stacked with an aperture size of 1.4 × 1.4 mm2 and assembled in a customized two-lumen 10-Fr catheter for intravascular sonothrombolysis. The treatment process was monitored with internal-illumination photoacoustic tomography (II-PAT), a hybrid imaging modality that combines the rich contrast of optical absorption and the deep penetration of ultrasound detection. With intravascular light delivery using a thin optical fiber integrated with the intravascular catheter, II-PAT overcomes the penetration depth limited by strong optical attenuation of tissue. In-vitro PAT-guided sonothrombolysis experiments were carried out with synthetic blood clots embedded in tissue phantom. Clot position, shape, stiffness, and oxygenation level can be estimated by II-PAT at clinically relevant depth of ten centimeters. Our findings have demonstrated the feasibility of the proposed PAT-guided intravascular sonothrombolysis with real-time feedback during the treatment process.

High-fidelity deep functional photoacoustic tomography enhanced by virtual point sources.

Photoacoustic tomography (PAT), a hybrid imaging modality that acoustically detects the optical absorption contrast, is a promising technology for imaging hemodynamic functions in deep tissues far beyond the traditional optical microscopy. However, the most clinically compatible PAT often suffers from the poor image fidelity, mostly due to the limited detection view of the linear ultrasound transducer array. PAT can be improved by employing highly-absorbing contrast agents such as droplets and nanoparticles, which, however, have low clinical translation potential due to safety concerns and regulatory hurdles imposed by these agents. In this work, we have developed a new methodology that can fundamentally improve PAT's image fidelity without hampering any of its functional capability or clinical translation potential. By using clinically-approved microbubbles as virtual point sources that strongly and isotropically scatter the local pressure waves generated by surrounding hemoglobin, we can overcome the limited-detection-view problem and achieve high-fidelity functional PAT in deep tissues, a technology referred to as virtual-point-source PAT (VPS-PAT). We have thoroughly investigated the working principle of VPS-PAT by numerical simulations and in vitro phantom experiments, clearly showing the signal origin of VPSs and the resultant superior image fidelity over traditional PAT. We have also demonstrated in vivo applications of VPT-PAT for functional small-animal studies with physiological challenges. We expect that VPS-PAT can find broad applications in biomedical research and accelerated translation to clinical impact.

Deep thrombosis characterization using photoacoustic imaging with intravascular light delivery.

Venous thromboembolism (VTE) is a condition in which blood clots form within the deep veins of the leg or pelvis to cause deep vein thrombosis. The optimal treatment of VTE is determined by thrombus properties such as the age, size, and chemical composition of the blood clots. The thrombus properties can be readily evaluated by using photoacoustic computed tomography (PACT), a hybrid imaging modality that combines the rich contrast of optical imaging and deep penetration of ultrasound imaging. With inherent sensitivity to endogenous chromophores such as hemoglobin, multispectral PACT can provide composition information and oxygenation level in the clots. However, conventional PACT of clots relies on external light illumination, which provides limited penetration depth due to strong optical scattering of intervening tissue. In our study, this depth limitation is overcome by using intravascular light delivery with a thin optical fiber. To demonstrate in vitro blood clot characterization, clots with different acuteness and oxygenation levels were placed underneath ten-centimeter-thick chicken breast tissue and imaged using multiple wavelengths. Acoustic frequency analysis was performed on the received PA channel signals, and oxygenation level was estimated using multispectral linear spectral unmixing. The results show that, with intravascular light delivery, clot oxygenation level can be accurately measured, and the clot age can thus be estimated. In addition, we found that retracted and unretracted clots had different acoustic frequency spectrum. While unretracted clots had stronger high frequency components, retracted clots had much higher low frequency components due to densely packed red blood cells. The PACT characterization of the clots was consistent with the histology results and mechanical tests.