Photoacoustic tomography (PAT) can create multiscale multicontrast images of living biological structures ranging from organelles to organs. This emerging technology overcomes the high degree of scattering of optical photons in biological tissue by making use of the photoacoustic effect. Light absorption by molecules creates a thermally induced pressure jump that launches ultrasonic waves, which are received by acoustic detectors to form images. Different implementations of PAT allow the spatial resolution to be scaled with the desired imaging depth in tissue while a high depth-to-resolution ratio is maintained. As a rule of thumb, the achievable spatial resolution is on the order of 1/200 of the desired imaging depth, which can reach up to 7 centimeters. PAT provides anatomical, functional, metabolic, molecular, and genetic contrasts of vasculature, hemodynamics, oxygen metabolism, biomarkers, and gene expression. We review the state of the art of PAT for both biological and clinical studies and discuss future prospects.

Photoacoustic Tomography: In Vivo Imaging from Organelles to Organs

Photoacoustic (PA) imaging, also called optoacoustic imaging, is a new biomedical imaging modality based on the use of laser-generated ultrasound that has emerged over the last decade. It is a hybrid modality, combining the high-contrast and spectroscopic-based specificity of optical imaging with the high spatial resolution of ultrasound imaging. In essence, a PA image can be regarded as an ultrasound image in which the contrast depends not on the mechanical and elastic properties of the tissue, but its optical properties, specifically optical absorption. As a consequence, it offers greater specificity than conventional ultrasound imaging with the ability to detect haemoglobin, lipids, water and other light-absorbing chomophores, but with greater penetration depth than purely optical imaging modalities that rely on ballistic photons. As well as visualizing anatomical structures such as the microvasculature, it can also provide functional information in the form of blood oxygenation, blood flow and temperature. All of this can be achieved over a wide range of length scales from micrometres to centimetres with scalable spatial resolution. These attributes lend PA imaging to a wide variety of applications in clinical medicine, preclinical research and basic biology for studying cancer, cardiovascular disease, abnormalities of the microcirculation and other conditions. With the emergence of a variety of truly compelling in vivo images obtained by a number of groups around the world in the last 2–3 years, the technique has come of age and the promise of PA imaging is now beginning to be realized. Recent highlights include the demonstration of whole-body small-animal imaging, the first demonstrations of molecular imaging, the introduction of new microscopy modes and the first steps towards clinical breast imaging being taken as well as a myriad of in vivo preclinical imaging studies. In this article, the underlying physical principles of the technique, its practical implementation, and a range of clinical and preclinical applications are reviewed.

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Biomedical photoacoustic imaging

The nonradiative conversion of light energy into heat (photothermal therapy, PTT) or sound energy (photoacoustic imaging, PAI) has been intensively investigated for the treatment and diagnosis of cancer, respectively. By taking advantage of nanocarriers, both imaging and therapeutic functions together with enhanced tumour accumulation have been thoroughly studied to improve the pre-clinical efficiency of PAI and PTT. In this review, we first summarize the development of inorganic and organic nano photothermal transduction agents (PTAs) and strategies for improving the PTT outcomes, including applying appropriate laser dosage, guiding the treatment via imaging techniques, developing PTAs with absorption in the second NIR window, increasing photothermal conversion efficiency (PCE), and also increasing the accumulation of PTAs in tumours. Second, we introduce the advantages of combining PTT with other therapies in cancer treatment. Third, the emerging applications of PAI in cancer-related research are exemplified. Finally, the perspectives and challenges of PTT and PAI for combating cancer, especially regarding their clinical translation, are discussed. We believe that PTT and PAI having noteworthy features would become promising next-generation non-invasive cancer theranostic techniques and improve our ability to combat cancers.

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Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer

Optical microscopy has been a fundamental tool of biological discovery for more than three centuries, but its in vivo tissue imaging ability has been restricted by light scattering to superficial investigations, even when confocal or multiphoton methods are used. Recent advances in optical and optoacoustic (photoacoustic) imaging now allow imaging at depths and resolutions unprecedented for optical methods. These abilities are increasingly important to understand the dynamic interactions of cellular processes at different systems levels, a major challenge of postgenome biology. This Review discusses promising photonic methods that have the ability to visualize cellular and subcellular components in tissues across different penetration scales. The methods are classified into microscopic, mesoscopic and macroscopic approaches, according to the tissue depth at which they operate. Key characteristics associated with different imaging implementations are described and the potential of these technologies in biological applications is discussed.

Going deeper than microscopy: the optical imaging frontier in biology

Photoacoustic tomography (PAT) is probably the fastest-growing area of biomedical imaging technology, owing to its capacity for high-resolution sensing of rich optical contrast in vivo at depths beyond the optical transport mean free path (~1 mm in human skin). Existing high-resolution optical imaging technologies, such as confocal microscopy and two-photon microscopy, have had a fundamental impact on biomedicine but cannot reach the penetration depths of PAT. By utilizing low ultrasonic scattering, PAT indirectly improves tissue transparency up to 1000-fold and consequently enables deeply penetrating functional and molecular imaging at high spatial resolution. Furthermore, PAT promises in vivo imaging at multiple length-scales; it can image subcellular organelles to organs with the same contrast origin — an important application in multiscale systems biology research.

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Multiscale photoacoustic microscopy and computed tomography.

Photoacoustic imaging has great potential for identifying vascular regions for clinical imaging. In addition to assessing angiogenesis in cancers, there are many other disease processes that result in increased vascularity that present novel targets for photoacoustic imaging. Doppler imaging can provide good localization of large vessels, but poor imaging of small or low flow speed vessels and is susceptible to motion artifacts. Photoacoustic imaging can provide visualization of small vessels, but due to the filtering effects of ultrasound transducers, only shows the edges of large vessels. Thus, we have combined photoacoustic imaging with ultrasound power Doppler to provide contrast agent- free vascular imaging. We use a research-oriented ultrasound array system to provide interlaced ultrasound, Doppler, and photoacoustic imaging. This system features realtime display of all three modalities with adjustable persistence, rejection, and compression. For ease of use in a clinical setting, display of each mode can be disabled. We verify the ability of this system to identify vessels with varying flow speeds using receiver operating characteristic curves, and find that as flow speed falls, photoacoustic imaging becomes a much better method for identifying blood vessels. We also present several in vivo images of the thyroid and several synovial joints to assess the practicality of this imaging for clinical applications.

Real-time clinically oriented array-based in vivo combined photoacoustic and power Doppler imaging

Photoacoustic imaging has emerged as a promising technique for visualizing optically absorbing structures with
ultrasonic spatial resolution. Since it relies on optical absorption of tissues, photoacoustic imaging is particularly
sensitive to vascular structures even at the micro-scale. Power Doppler ultrasound can be used to detect moving blood
irrespective of Doppler angles. However, the sensitivity may be inadequate to detect very small vessels with slow flow
velocities. In this work, we merge these two synergistic modalities and compare power Doppler ultrasound images with
high-contrast photoacoustic images. We would like to understand the advantages and disadvantages of each technique
for assessing microvascular density, an important indicator of disease status. A combined photoacoustic and highfrequency
ultrasound system has been developed. The system uses a swept-scan 25 MHz ultrasound transducer with
confocal dark-field laser illumination optics. A pulse-sequencer enables ultrasonic and laser pulses to be interlaced so
that photoacoustic and Doppler ultrasound images are co-registered. Experiments have been performed on flow
phantoms to test the capability of our system and signal processing methods. Work in progress includes in vivo color
flow mapping. This combined system will be used to perform blood oxygen saturation and flow estimations, which will
provide us with the parameters to estimate the local rate of metabolic oxygen consumption, an important indicator for
many diseases.

Combined photoacoustic and high-frequency power Doppler ultrasound imaging

We present photoacoustic remote sensing and autofluorescence microscopy with surface excitation (PARS-AMUSE) system that combines several methodologies of optical imaging including absorption, scattering and radiative emission. We generate virtual hematoxylin and eosin (H&E) images from absorption and scattering data using a generative adversarial network for margin assessment and cancer grading with simultaneous metabolic measurements from the autofluorescence of NADH and FAD. This system utilizes a single excitation source for all three imaging modalities to minimize complexity and cost. Using this system, we aim to profile specific cancers and predict cancer aggression. 

Prostate needle biopsy metabolic analysis and virtual H&E microscopy using photoacoustic remote sensing and autofluorescence microscopy (Conference Presentation)

Using analytical calculations, a precise large signal equivalent circuit model of square CMUT dynamics was developed. The model predicts many intrinsic properties of a square CMUT cell including resonance frequency, phase and magnitude of the membrane displacement, membrane velocity, electrical conductance, collapse voltage, etc. ANSYS 3D finite element analysis (FEA) was used to validate the equivalent circuit model predictions by performing static, pre-stressed harmonic and nonlinear transient analysis. The model was designed and implemented in a circuit simulator and then compared with finite element methods (FEM) and experimental results. The results were compared with circular CMUT cells when the half-side-length of the square CMUT is assumed to be equal to the radii of the circular CMUT cell. A silicon-nitride standard sacrificial release process was used to fabricate the square CMUT cells. The experimental results obtained by a laser vibrometer were compared with circuit simulations and the results showed excellent agreements.

A nonlinear large signal equivalent circuit model for a square CMUT cell

We propose a method to measure blood pressure of small vessels non-invasively and in-vivo : by combining PA imaging with compression US. Using this method, we have shown pressure-lumen area tracking, as well as estimation of the internal vessel pressure, located 2 mm deep in tissue. Additionally, reperfusion can be tracked by measuring the total PA signal within a region of interest (ROI) after compression has been released. The ROI is updated using cross-correlation based displacement tracking 1 . The change in subcutaneous perfusion rates can be seen when the temperature of the hand of a human subject drops below the normal.

Roger J. Zemp

Papers

Real-time clinically oriented array-based in vivo combined photoacoustic and power Doppler imaging

Combined photoacoustic and high-frequency power Doppler ultrasound imaging

Prostate needle biopsy metabolic analysis and virtual H&E microscopy using photoacoustic remote sensing and autofluorescence microscopy (Conference Presentation)

A nonlinear large signal equivalent circuit model for a square CMUT cell

Compression-tracking photoacoustic perfusion and microvascular pressure measurements