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.

In the postgenomic era, imaging techniques are playing an important role in visualizing gene expression in vivo. This work represents the first demonstration of photoacoustic tomography (PAT) for reporter gene imaging. Rats inoculated with 9L/lacZ gliosarcoma tumor cells are imaged with PAT before and after injection of X-gal, a colorimetric assay for the lacZ-encoded enzyme β 
β
-galactosidase. Using far-red optical illumination, the genetically tagged tumors in rats are clearly visualized by PAT following the assay. The spatial resolution is quantified to be less than 400μm 
400μm
, while 500-nM-level sensitivity is demonstrated. With the future development of new absorption-based reporter gene systems, it is anticipated that photoacoustic technology will provide a valuable tool for molecular imaging research.

https://www.spiedigitallibrary.org/journals/journal-of-biomedical-optics/volume-12/issue-2/020504/Photoacoustic-imaging-of-lacZ-gene-expression-in-vivo/10.1117/1.2717531.pdf

Photoacoustic imaging of lacZ gene expression in vivo.

Elasto-optical refractive index modulation due to photoacoustic initial pressure transients produced significant reflection of a probe beam when the absorbing interface had an appreciable refractive index difference This effect was harnessed in a new form of non-contact optical resolution photoacoustic microscopy called photoacoustic remote sensing microscopy A non-interferometric system architecture with a low-coherence probe beam precludes detection of surface oscillations and other phase-modulation phenomenon The probe beam was confocal with a scanned excitation beam to ensure detection of initial pressure-induced intensity reflections at the subsurface origin where pressures are largest Phantom studies confirmed signal dependence on optical absorption, index contrast and excitation fluence In vivo imaging of superficial microvasculature and melanoma tumors was demonstrated with ~27±05 μm lateral resolution A new design for a photoacoustic microscope capable of high-quality, real-time in vivo imaging has been developed by scientists in Canada Parsin Hajireza and co-workers from the University of Alberta and the company Illumisonics report that, unlike other designs, their approach does not rely on interferometric detection of photoacoustic stress, which can be problematic Instead, it involves making time-varying intensity measurements of the reflection of a probe beam from the sample A high signal-to-noise ratio and a working distance of 25 centimetres between the sample and the system's objective lens are achievable The researchers demonstrate the potential of their scheme for biomedical applications by using to perform in vivo imaging of microvasculature and melanoma tumours in chicken embryos with a spatial resolution of 27 micrometres

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Non-interferometric photoacoustic remote sensing microscopy

A computationally efficient model capable of simulating finite-amplitude ultrasound beam propagation in water and in tissue from phased linear arrays and other transducers of arbitrary quasiplanar geometry is described. It is based on a second-order operator splitting approach [Tavakkoli et al., J. Acoust. Soc. Am. 104, 2061-2072 (1998)], with a fractional step-marching scheme, whereby the effects of diffraction, attenuation, and nonlinearity can be computed independently over incremental steps. This approach is an extension to that of Christopher and Parker [J. Acoust. Soc. Am. 90, 507-521; 90, 488-499 (1991)], wherein linear and nonlinear effects are propagated separately over incremental steps, and the computation of the diffractive substeps are based on an angular spectrum technique with a modified sampling scheme for accurate and efficient implementation of diffractive propagation from nonradially symmetric sources. Results of the model are compared with published data. Predicted field profiles for nonlinear propagation in tissue from realistic array transducers using the pulse inversion method are presented.

Modeling of nonlinear ultrasound propagation in tissue from array transducers

Quantitative imaging of optical properties of biological tissues with high resolution has been a long-sought-after goal of many research groups. Photoacoustic imaging is a hybrid bio-optical imaging technique offering optical absorption contrast with ultrasonic spatial resolution. While photoacoustic methods offer significant promise for high-resolution optical imaging, quantification has thus far proved challenging. In this paper, a noniterative reconstruction technique for producing quantitative photoacoustic images of absorption perturbations is introduced for the case when the optical properties of the turbid background are known and when multiple optical illumination locations are used. Through theoretical developments and computational examples it is demonstrated that multiple-optical-source photoacoustic imaging can produce quantitative optical absorption reconstructions. The combination of optical and photoacoustic measurements is shown to yield improved reconstruction stability.

Quantitative photoacoustic tomography with multiple optical sources

Visualization of microvascular networks could provide new information about function and disease. We demonstrate the capabilities of a 30-MHz ultrasound array system for photoacoustic microscopy of small 300 m vessels in a rat. 3D images obtained by trans- lating the array in the elevation direction are compared with photographs of excised skin. The system is shown to have 100-m lateral resolution, 25-m axial resolution, and 3-mm imaging depth. To our knowledge this is the first report on photoacoustic microscopy of the microvas- culature with a high-frequency array transducer. It is an- ticipated that the system can be used for studying and diagnosing a number of diseases including cancer, athero- sclerosis, dermatological disorders, and peripheral mi- crovascular complications in diabetes. © 2007 Society of Photo-

https://www.spiedigitallibrary.org/journals/journal-of-biomedical-optics/volume-12/issue-1/010501/Photoacoustic-imaging-of-the-microvasculature-with-a-high-frequency-ultrasound/10.1117/1.2709850.pdf

Roger J. Zemp

Papers

Photoacoustic imaging of lacZ gene expression in vivo.

Non-interferometric photoacoustic remote sensing microscopy

Modeling of nonlinear ultrasound propagation in tissue from array transducers

Quantitative photoacoustic tomography with multiple optical sources

Photoacoustic imaging of the microvasculature with a high-frequency ultrasound array transducer.