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.

Delay-and-sum beamforming (DSB) of photoacoustic data does not incorporate a priori spatial sparsity of the imaging target. By incorporating this information into beamforming for limited-view photoacoustic computed tomography, we experimentally obtained enhanced resolution images of wires at a depth of 8.5 mm in a tissue mimicking scattering medium. Using a 21 MHz transducer, we improved the resolution from the 200 to 250 μm achieved by DSB to 75 μm. The sparsity-based technique also generated a cleaner image with a background signal level of roughly −50 dB, much lower than the roughly −18 dB background signal level of DSB.

Sparsity-based reconstruction for super-resolved limited-view photoacoustic computed tomography deep in a scattering medium.

While photoacoustic imaging is capable of producing high-resolution biomedical images with optical absorption contrast, optical property quantification has thus far remained challenging. One reason for this is that laser-induced photoacoustic signal amplitudes are proportional to not only the local optical absorption coefficient, but also the local laser fluence in the tissue. Unfortunately, local laser fluence is often unknown, but could possibly be estimated if local bulk tissue optical properties were known. One method to estimate tissue optical properties is a technique known as oblique incidence diffuse reflectance (OIR). We report on an integrated OIR and photoacoustic imaging system and demonstrate, using phantom experiments, improved ability to quantitatively estimate optical properties of a turbid medium.

https://www.spiedigitallibrary.org/journals/journal-of-biomedical-optics/volume-15/issue-4/046016/Combined-photoacoustic-and-oblique-incidence-diffuse-reflectance-system-for-quantitative/10.1117/1.3470336.pdf

Combined photoacoustic and oblique-incidence diffuse reflectance system for quantitative photoacoustic imaging in turbid media

The microfabrication processes for sacrificial-release-based capacitive micromachined ultrasound transducer arrays are provided with an emphasis on top-orthogonal-to-bottom electrode 2-D arrays. These arrays have significant promise for high-quality 3-D imaging with reduced wiring complexity compared with fully wired arrays. The protocols and best practices are outlined in significant detail along with design considerations and notes of caution for pitfalls and factors impacting yield.

Fabrication of Linear Array and Top-Orthogonal-to-Bottom Electrode CMUT Arrays With a Sacrificial Release Process

Novel multi-frequency Capacitive Micromachined Ultrasound Transducer (CMUT) arrays with interlaced low and high-frequency elements are investigated for novel imaging-therapy applications. Our interlaced CMUTs are designed with device dimensions smaller than operating wavelengths. This permits low- and high-frequency CMUT cells to be interlaced monolithically on a scale smaller than the array wavelengths. This dense interlacing scheme thus offers the promise of co-registered dual-frequency-band operation with minimal deleterious grating lobes and with maximal overlap of low- and high-frequency beams.

Multi-frequency CMUT arrays for imaging-therapy applications

Histopathology of lipid-rich tissues is often a difficult endeavor, owing to the limited tissue processing workflows that can appropriately preserve tissue while keeping fatty deposits intact. Here, we present the first usage of near-infrared (NIR) photoacoustic remote sensing (PARS) to achieve imaging contrast from lipids without the need for exogenous stains or labels. In our system, the facile production of 1225 nm excitation pulses is achieved by the stimulated Raman scattering of a 1064 nm source propagating through an optical fiber. PARS-based detection is achieved by monitoring the change in the scattering profile of a co-aligned 1550 nm continuous-wave interrogation beam in response to absorption of the 1225 nm light by lipids. Our non-contact, reflection-mode approach can achieve a FWHM resolution of up to 0.96 µm and signal-to-noise ratios as high as 45 dB from carbon fibers and 9.7 dB from a lipid phantom. NIR-PARS offers a promising approach to image lipid-rich samples with a simplified workflow.

Roger J. Zemp

Papers

Sparsity-based reconstruction for super-resolved limited-view photoacoustic computed tomography deep in a scattering medium.

Combined photoacoustic and oblique-incidence diffuse reflectance system for quantitative photoacoustic imaging in turbid media

Fabrication of Linear Array and Top-Orthogonal-to-Bottom Electrode CMUT Arrays With a Sacrificial Release Process

Multi-frequency CMUT arrays for imaging-therapy applications

Label-free lipid contrast imaging using non-contact near-infrared photoacoustic remote sensing microscopy