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 remote sensing (PARS) microscopy suffers from slow imaging speeds as a result of so far being an exclusively laser scanning microscopy-based technique. Here we introduce a camera-based PARS approach using a 10 million frames-per-second camera together with oblique 532nm excitation and white-light interrogation. 2mm x 1.2mm images of 20µm diameter gold bonding wires are obtained in fractions of a second albeit with lower resolution. Using these wide-field images, regions-of-interest can be established. Additionally, the observation of supersonic wavefronts suggest the generation of shockwaves. This observation is used to derive an empirical model for the time evolution of PARS signals. 

Towards high-speed camera-based parallelized widefield photoacoustic remote sensing microscopy

Fixed-point iteration shows promise for quantitative reconstruction of optical absorption in photoacoustic tomography. However, there are issues that prevent the technique from being practical including: non-uniqueness of scattering and absorption profiles, divergence with over-iteration, and sensitivity to noise. Multiple illumination has been proposed to deal with the first problem, and may help with the second. The issue of noise may be balanced out by increasing the regularization parameter at the expense of the exactness of the reconstruction. In a multiple-illumination setup with a circular geometry where fluence is abundant, using a patterned illumination with a decoding step may provide an alternative which will boost SNR. We present a simple sequence of patterned illuminations based on an S-sequence that serves to improve SNR. While the forward model of the iterative method may be applied directly to the patterned excitations, including the decoding step improves SNR in an individual image by a factor equal to the size of the S-sequence, thus greatly improving convergence for a given value of regularization and SNR. For example, with 15 illuminations, 50-60dB noise levels with S-sequence patterned illuminations gives similar simulated performance to the 70dB case with single-source illuminations. This technique will allow the application of fixed-point iteration techniques in a broader range of SNR conditions without resorting to averaging.

S-sequence patterned illumination for fixed-point iterative multiple illumination photoacoustic tomography

A realtime portable optical- resolution photoacoustic microscopy system is demonstrated. This system takes advantage of 2D galvanometer mirrors, a fiber bundle with several thousand single mode fibers, a pair of refocusing lenses and a unique portable probe. In vitro phantom studies indicate ~7μm lateral resolution. Also, the ability of this system for in vivo studies is demonstrated by imaging the microvasculature in a Swiss Webster mouse ear. The proposed system may improve the usability of optical-resolution photoacoustic microscopy for potential clinical and preclinical applications.

Realtime portable in vivo optical-resolution photoacoustic microscopy

Top orthogonal to bottom electrode (TOBE) arrays, also known as row–column arrays, hold great promise for fast high-quality volumetric imaging. Bias-voltage-sensitive TOBE arrays based on electrostrictive relaxors or micromachined ultrasound transducers can enable readout from every element of the array using only row and column addressing. However, these transducers require fast bias-switching electronics which are not part of a conventional ultrasound system and are nontrivial. Here we report on the first modular bias-switching electronics enabling transmit, receive, and biasing on every row and every column of TOBE arrays, supporting up to 1024 channels. We demonstrate the performance of these arrays by connection to a transducer testing interface board (IB) and demonstrate 3-D structural imaging of tissue and 3-D power Doppler imaging of phantoms with real-time B-scan imaging and reconstruction rates. Our developed electronics enable interfacing of bias-switchable TOBE arrays to channel-domain ultrasound platforms with software-defined reconstruction for next-generation 3-D imaging at unprecedented scales and imaging rates.

https://ieeexplore.ieee.org/ielx7/58/7307696/10049389.pdf

High-Voltage Bias-Switching Electronics for Volumetric Imaging Using Electrostrictive Row–Column Arrays

Plane wave methods for ultrafast ultrasound imaging suffer from a low signal to noise ratio (SNR) and a limited field of view at greater imaging depths. Imaging using multiple focused coded beams in parallel is one strategy for high speed imaging that may improve on these limitations. However, the SNR and resolution of this strategy are degraded by the interference between the beams transmitted in parallel. We aim to reduce this interference while retaining acceptable axial resolution by careful design of the coded beams. To ensure good axial resolution and to increase flexibility of code design, we use two transmit events to form each set of lines in the image. This implies an increase in imaging speed of approximately K=2, where K is the number of beams fired in parallel. To decode channel data we use a matched filter, summing cross-correlation results over each pair of transmit events. As a result, the interference between two beams fired in parallel is dictated by the magnitude of the sum of cross-correlations between parallel beam encoding patterns. We have constructed a metric based on this idea, and optimized coded beams for this metric using the sequential quadratic programming capabilities of MATLAB's nonlinear optimization toolbox. Using our optimization framework, we have generated codes that allow for very low interference between two simultaneously transmitted parallel beams. Our optimization framework also enables generation of lowerinterference codes for many simultaneous parallel focal zones, compared to randomly selected codes. In simulation, we found that using optimized codes reduces the clutter associated with parallel transmission, and that the optimized coded imaging strategy is capable of generating images with higher contrast than those acquired at the same frame rate by plane wave imaging.

Roger J. Zemp

Papers

Towards high-speed camera-based parallelized widefield photoacoustic remote sensing microscopy

S-sequence patterned illumination for fixed-point iterative multiple illumination photoacoustic tomography

Realtime portable in vivo optical-resolution photoacoustic microscopy

High-Voltage Bias-Switching Electronics for Volumetric Imaging Using Electrostrictive Row–Column Arrays

Optimization strategies and neighbour-pair complementary codes for massively parallel focal-zone ultrafast ultrasound