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.

An ideal observer model is developed for the task of detecting blood perfusing or flowing through tissue. The ideal observer theory relies on a linear systems model that describes tissue and blood object functions and electronic noise as random processes. When aliasing is minimal, the system is characterized by a quantity similar to Noise-Equivalent Quanta used in photon imaging modalities. A simple 1-D model is used to illustrate the effect of the system and object parameters on task performance. Velocity and decorrelation are seen to be advantageous for detection. Aliasing can degrade performance. The ideal observer model provides a framework for assessing the performance of Power Doppler ultrasound systems, and may aid in their design.

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Ideal observer model for detection of blood perfusion and flow using ultrasound.

Photoacoustic remote sensing (PARS) is a novel all-optical imaging modality that allows for non-contact detection of initial photoacoustic pressures. Using 266-nm excitation pulses, ultraviolet PARS (UV-PARS) has previously demonstrated imaging contrast for cell nuclei in histological samples with <400nm resolution. In prior PARS-based imaging schemes, the signal amplitude at an interrogation point was determined by the maximum deflection from the DC scattering signal in response to a pulsed excitation. This method, however, does not take into consideration additional information encoded in the frequency domain of the recorded PARS signals. Here, we present a frequency domain technique called F-mode PARS that can be used to generate images with nuclear and cytoplasmic enhanced contrast, enabling label-free virtual hematoxylin-and-eosin-like microscopy, using only a single excitation wavelength. With F-mode processing, we have been able to demonstrate contrast-to-noise ratios of up to 38 dB between cell nuclei and surrounding cytoplasm, which represents up to a 25-dB improvement over previous implementations of UV-PARS systems.

F-mode ultraviolet photoacoustic remote sensing for label-free virtual H&E histopathology using a single excitation wavelength.

In this paper the feasibility of optical-resolution photoacoustic micro-endoscopy (OR-PAME) using image guide
fibers and a unique fiber laser system is demonstrated. The image guide consists of 30,000 individual fibers in a
bundle 800 μm in diameter and the diode-pumped, pulsed Ytterbium fiber laser can provide repetition rates up to
600 kHz. Phantom studies indicate 7+/-2 μm resolution. The compact, flexible nature of the image guide and the
small footprint of the apparatus make it ideal for photoacoustic micro-endoscopy, as well as increasing the usability
of OR-PAM for potential clinical applications.

Optical-resolution photoacoustic micro-endoscopy using image-guide fibers and fiber laser technology

Reflection-mode multiple-illumination photoacoustic sensing to estimate optical properties

Capacitive micromachined ultrasonic transducers (CMUTs) promise many advantages over traditional piezoelectric transducers such as the potential to construct large, cost-effective 2-D arrays. To avoid wiring congestion issues associated with fully wired arrays, top-orthogonal-to-bottom electrode (TOBE) CMUT array architectures have proven to be a more practical alternative, using only $2N$ wires for an $N \times N$ array. Optimally designing a TOBE CMUT array is a significant challenge due to the range of parameters from the device level up to the operating conditions of the entire array. Since testing many design variations can be prohibitively expensive, a simulation approach accounting for both the small and large-scale array characteristics of TOBE arrays is essential. In this paper, we demonstrate large-scale TOBE CMUT array simulations using a nonlinear CMUT lumped-circuit model. We investigate the performance of the array with different CMUT design parameters and array operating conditions. These simulated results are then compared with measurements of TOBE arrays fabricated using a sacrificial release process.

Roger J. Zemp

Papers

Ideal observer model for detection of blood perfusion and flow using ultrasound.

F-mode ultraviolet photoacoustic remote sensing for label-free virtual H&E histopathology using a single excitation wavelength.

Optical-resolution photoacoustic micro-endoscopy using image-guide fibers and fiber laser technology

Reflection-mode multiple-illumination photoacoustic sensing to estimate optical properties

Large-Scale Nonlinear Lumped and Integrated Field Simulations of Top-Orthogonal-to-Bottom-Electrode CMUT Architectures