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.

Traditionally dielectric charging has been viewed as an undesirable feature of Capacitive Micromachined Ultrasound Transducers (CMUTs) because charging can alter performance of devices and lead to permanent collapse. We introduce a beneficial aspect of dielectric charging in CMUTs. We demonstrate CMUTs that may be pre-charged with a shift in collapse voltage so that at zero applied bias voltage they experience an electrostatic deflection due to trapped dielectric charge. We demonstrate efficient pre-collapse operation at zero applied bias voltage with exceptional long-term reliability. Similar existing strategies for pre-charging CMUTs were not implemented for diagnostic frequencies for immersion or tissue-coupled applications.

Pre-charged CMUTs with efficient low-bias voltage operation for medical applications

Researchers have been using single element transducers for photoacoustic microscopy (PAM), but such systems
have limited depth of field due to a single focus. The aim for this project was to develop a high-frequency annular
array transducer for improved depth-of-field PAM. We have designed a concave 40 MHz ultrasound transducer
which has 8 annular array elements with equal area. The outer ring is 12 mm in diameter, the geometric focus is 12
mm, and the space between each annulus is 100 μm. The array was fabricated by lithographically patterning
metalized polyimide film to define back electrodes and signal leads. 9-micron-PVDF film was then press-fit into the
array pattern with epoxy as a backing material and a single drop of epoxy as a bonding layer. The array exhibits high
sensitivity to high-frequency photoacoustic signals. Dynamic focusing of amplified and digitized signals permits
extended depth-of-field imaging compared to the single-element transducer case. Dark-field light-delivery and 
3-axis motorized scanning permits 3-D photoacoustic microscopy. Imaging performance in phantoms is discussed.

Improved depth-of-field photoacoustic microscopy with a custom high-frequency annular array transducer

In this paper we introduce a novel optical resolution photoacoustic micro-endoscopy system using GRIN-lens
focusing. This real-time imaging system takes advantage of an image guide fiber consisting of 100,000 individual
single-mode fibers in a 1.4-mm-diameter bundle, and a 532-nm fiber laser with repetition-rates as high as 600 kHz.
Fast scanning mirrors were used to scan the entire image guide fiber allowing for the maximum field-of-view. The
ability of the proposed system is demonstrated using both phantom and in vivo studies. The system offers <7 μm
lateral spatial resolution and several volumetric/C-scans per second frame-rate. The proposed setup can be inserted
into the body due to the flexible nature of the image guide and micron-scale footprint of the apparatus.

In vivo imaging with GRIN-lens optical resolution photoacoustic micro-endoscopy

We describe the use of monolithic, buckled-dome cavities as ultrasound sensors. Patterned delamination within a compressively stressed thin film stack produces high-finesse plano-concave optical resonators with sealed and empty cavity regions. The buckled mirror also functions as a flexible membrane, highly responsive to changes in external pressure. Owing to their efficient opto-acousto-mechanical coupling, thermal-displacement-noise limited sensitivity is achieved at low optical interrogation powers and for modest optical (Q ∼ 103) and mechanical (Q ∼ 102) quality factors. We predict and verify broadband (up to ∼ 5 MHz), air-coupled ultrasound detection with noise-equivalent pressure (NEP) as low as ∼ 30-100 µPa/Hz1/2. This corresponds to an ultrasonic force sensitivity ∼ 2 × 10-13 N/Hz1/2 and enables the detection of MHz-range signals propagated over distances as large as ∼ 20 cm in air. In water, thermal-noise-limited sensitivity is demonstrated over a wide frequency range (up to ∼ 30 MHz), with NEP as low as ∼ 100-800 µPa/Hz1/2. These cavities exhibit a nearly omnidirectional response, while being ∼ 3-4 orders of magnitude more sensitive than piezoelectric devices of similar size. Easily realized as large arrays and naturally suited to direct coupling by free-space beams or optical fibers, they offer significant practical advantages over competing optical devices, and thus could be of interest for several emerging applications in medical and industrial ultrasound imaging.

Ultrasound sensing at thermomechanical limits with optomechanical buckled-dome microcavities.

3D Ultrasound systems present several technical challenges, particularly the large number of elements in a 2D array, high electrical impedance, and image acquisition time. Crossed electrode arrays address some of these issues, especially the huge reduction in number of elements. However, creating a two-way focused 3D image in real-time is difficult with these arrays because azimuth and elevation dimensions cannot be beamformed at the same time. This typically forces one to use a synthetic aperture approach which is inherently slow and requires increased beamforming complexity over a 1D array. We have developed a new, fast and simple 3D imaging approach referred to as Simultaneous Azimuth and Fresnel Elevation (SAFE) compounding. The principle behind this technique is to perform conventional plane wave compounding with the top set of electrodes, while implementing a reconfigurable Fresnel elevation lens with the bottom electrodes. While a Fresnel lens would usually result in unacceptable secondary lobe levels, these lobes can be suppressed by compounding different Fresnel patterns. Since plane wave imaging already compounds the same slice repeatedly, the elevation Fresnel lens can be simultaneously compounded to increase the beam quality, resulting in no loss in frame rate. In this study, the design, fabrication, and characterization of a crossed electrode array based on an electrostrictive ceramic (eg. Pulse polarity depends on a DC bias) is presented.

Roger J. Zemp

Papers

Pre-charged CMUTs with efficient low-bias voltage operation for medical applications

Improved depth-of-field photoacoustic microscopy with a custom high-frequency annular array transducer

In vivo imaging with GRIN-lens optical resolution photoacoustic micro-endoscopy

Ultrasound sensing at thermomechanical limits with optomechanical buckled-dome microcavities.

Fabrication and performance of a 128-element crossed-electrode relaxor array, for a novel 3D imaging approach