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.

We present an algorithm for quantitative photoacoustic tomography based on minimizing an error functional between measured photoacoustic channel data and a calculated forward model. Simulations using multiple illuminations show improved conditioning over single illumination.

Iterative Algorithm for Multiple Illumination Photoacoustic Tomography using Transducer Channel Data

Recently Top-Orthogonal-to-Bottom Electrode (TOBE) 2D CMUT arrays were introduced. These arrays offered the possibility of 3D imaging without requiring a fully-wired array, however, previously proposed imaging schemes suffered from speed or resolution limitations. Here we propose a new imaging scheme which we call Fast Orthogonal Row-Column Electronic Scanning (FORCES). This new approach takes advantage of the bias-sensitivity of CMUTs to enable high-quality and fast B-scan imaging.

Practical S-Sequence aperture coding schemes for volumetric imaging with Top Orthogonal to Bottom Electrode (TOBE) arrays

Following resection of cancerous tissues, specimens are excised from the surgical margins to be examined post-operatively for the presence of residual cancer cells. Hematoxylin and eosin (H&E) staining is the gold standard of histopathological assessment. Ultraviolet photoacoustic microscopy (UV-PARS), combined with scattering microscopy, provides virtual nuclei and cytoplasm contrast similar to H&E staining. A generative adversarial network (GAN) deep learning approach, specifically a CycleGAN, was used to perform style transfer to improve the histological realism of UV-PARS generated images. Post-CycleGAN images are easier for a pathologist to examine and can be input into existing machine learning pipelines for H&E-stained images. 

Improving the histological realism of ultraviolet photoacoustic remote sensing microscopy images using a deep learning-based generative adversarial network

Capacitive micromachined ultrasound transducers (CMUTs) have been investigated for over 25 years due to their promise for mass manufacturing and electronic co-integration. Previously, CMUTs were fabricated with many small membranes comprising a single transducer element. This, however, resulted in sub-optimal electromechanical efficiency and transmit performance, such that resulting devices were not necessarily competitive with piezoelectric transducers. Moreover, many previous CMUT devices were subject to dielectric charging and operational hysteresis that limited long-term reliability. Recently we demonstrated a CMUT architecture using a single long rectangular membrane per transducer element and novel electrode post structures. This architecture not only offers long-term reliability, but also provides performance advantages over previously published CMUT and piezoelectric arrays. The purpose of this paper is to highlight these performance advantages and provide details of the fabrication process, including the best practices to avoid common pitfalls. The objective is to provide sufficient detail to inspire a new generation of microfabricated transducers which could lead to performance gains of future ultrasound systems.

High-Performance Electrode-Post CMUTs: Fabrication Details and Best Practices.

In this work, a flexible transparent CMUT array is fabricated for through-illumination photoacoustic applications in which shape conformality is required. The array is composed of glass pieces with transparent structural layers on them, which are connected to each other via PDMS, making the array flexible. Unlike the previous flexible devices in the literature, the array is very robust to bending. The photoacoustic image of a wire target was successfully reconstructed using the fabricated flexible transparent CMUT array. The fabricated device offers promise for future photoacoustic tomography systems with through-array illumination. 

Roger J. Zemp

Papers

Iterative Algorithm for Multiple Illumination Photoacoustic Tomography using Transducer Channel Data

Practical S-Sequence aperture coding schemes for volumetric imaging with Top Orthogonal to Bottom Electrode (TOBE) arrays

Improving the histological realism of ultraviolet photoacoustic remote sensing microscopy images using a deep learning-based generative adversarial network

High-Performance Electrode-Post CMUTs: Fabrication Details and Best Practices.

Through-illumination photoacoustic imaging using flexible transparent CMUT arrays