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.

Ultrasound-based strain imaging is an exciting new medical imaging technique that is capable of revealing soft tissue regions that stiffen early in the development of disease processes. In one important application, breast imaging, lesion visibility is limited primarily by decorrelation noise. Accumulating measurements from many small compressions was found to be most effective at reducing decorrelation noise without reducing contrast or spatial resolution provided that we also applied coded pulse excitation to the probing ultrasonic transmission. Improvements were greatest when the echo signal-to-noise ratio (eSNR) was low. To predict the quality of strain estimates when designing systems, generalized coherence functions and the corresponding displacement variance bounds were derived. The contribution of this paper is to extend that treatment to include coded excitation and multicompression techniques. The advantages of coded excitation/multicompression techniques are demonstrated by imaging tissue-like phantoms and comparing results with conventional short pulse/single compression methods.

Practical error bounds for ultrasonic strain estimation using coded excitation

Quantitative photoacoustic microscopy (qPAT) is challenging. We present an algorithm which consecutively reconstructs absorption and scattering coefficient distributions with an iterative scheme in multiple-illumination photoacoustic tomography (MIPAT). In each iteration, the absorption distribution is estimated with the least-squares fixed-point iteration method. Then the diffusion coefficient is estimated with an updated version of optical fluence based on the previously modified absorption information. This procedure is repeated till an acceptable results is achieved. Simulation examples demonstrate the capability of this method in faithfully recovering the absorption and diffusion coeffient distributions, and fast convergence.

A consecutive reconstruction strategy for estimating absorption and scattering coefficient distribution in multiple-illumination photoacoustic tomography (MIPAT)

We developed a novel colony-based photoacoustic screening method to screen and evolve a chromoprotein. The improved protein was used as genetically-encoded photoacoustic reporter and as a dark acceptor in FRET-based caspase-3 biosensors and Ca2+ biosensors.

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Engineering a Chromoprotein Reporter for Photoacoustic Imaging and Biosensing Applications

Deep learning-enabled realistic virtual histology with ultraviolet scattering and photoacoustic remote sensing microscopy

Photoacoustic imaging offers a new and complementary contrast mechanism to the traditional structural contrast
of ultrasound. While the combination of these two modes has been demonstrated in the past with single-element
transducers, array transducers offer clear advantages in both modes by eliminating mechanical scanning and
allowing image formation from a single excitation. Given the abundance of commercially available ultrasound
systems, it is desirable to use them as much as possible. However, these systems often only allow access to
beamformed RF data. We discuss the applicability of ultrasound beamformers for photoacoustic imaging, and
find that with only software-defined control over the speed of sound, walking aperture reconstruction is optimally
performed using a speed correction factor of 1.414. When sector-scanning is used, a different strategy is required.
We also demonstrate a new photoacoustic-ultrasound imaging system based on a Verasonics ultrasound array
system. The system streams raw channel data to a 6-core PC at up to 1.4GB/s via PCI-Express, allowing
interlaced ultrasound and photoacoustic data to be acquired and reconstructed at realtime rates. Using an L7-4
linear array transducer, we demonstrate the performance of this system and discuss potential applications. The
system should provide new opportunities for clinical and pre-clinical imaging.

Roger J. Zemp

Papers

Practical error bounds for ultrasonic strain estimation using coded excitation

A consecutive reconstruction strategy for estimating absorption and scattering coefficient distribution in multiple-illumination photoacoustic tomography (MIPAT)

Engineering a Chromoprotein Reporter for Photoacoustic Imaging and Biosensing Applications

Deep learning-enabled realistic virtual histology with ultraviolet scattering and photoacoustic remote sensing microscopy

Interlaced realtime channel-domain photoacoustic and ultrasound imaging