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

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.

Photoacoustic imaging of living subjects offers higher spatial resolution and allows deeper tissues to be imaged compared with most optical imaging techniques1,2,3,4,5,6,7. As many diseases do not exhibit a natural photoacoustic contrast, especially in their early stages, it is necessary to administer a photoacoustic contrast agent. A number of contrast agents for photoacoustic imaging have been suggested previously8,9,10,11,12,13,14,15, but most were not shown to target a diseased site in living subjects. Here we show that single-walled carbon nanotubes conjugated with cyclic Arg-Gly-Asp (RGD) peptides can be used as a contrast agent for photoacoustic imaging of tumours. Intravenous administration of these targeted nanotubes to mice bearing tumours showed eight times greater photoacoustic signal in the tumour than mice injected with non-targeted nanotubes. These results were verified ex vivo using Raman microscopy. Photoacoustic imaging of targeted single-walled carbon nanotubes may contribute to non-invasive cancer imaging and monitoring of nanotherapeutics in living subjects16. Photoacoustic imaging offers higher spatial resolution than most optical imaging techniques, but contrast agents are needed because many diseases in their early stages do not display a natural photoacoustic contrast. Using single-walled carbon nanotubes conjugated with a peptide as a contrast agent allows the non-invasive photoacoustic imaging of tumours in animals.

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Carbon nanotubes as photoacoustic molecular imaging agents in living mice.

This review describes the diffusion model for light transport in tissues and the medical applications of diffuse light. Diffuse optics is particularly useful for measurement of tissue hemodynamics, wherein quantitative assessment of oxy- and deoxy-hemoglobin concentrations and blood flow are desired. The theoretical basis for near-infrared or diffuse optical spectroscopy is developed, and the basic elements of diffuse optical tomography are outlined. We also discuss diffuse correlation spectroscopy, a technique whereby temporal correlation functions of diffusing light are transported through tissue and are used to measure blood flow. Essential instrumentation is described, and representative brain and breast functional imaging and monitoring results illustrate the workings of these new tissue diagnostics.

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Diffuse optics for tissue monitoring and tomography

The difficulty in delineating brain tumor margins is a major obstacle in the path toward better outcomes for patients with brain tumors. Current imaging methods are often limited by inadequate sensitivity, specificity and spatial resolution. Here we show that a unique triple-modality magnetic resonance imaging-photoacoustic imaging-Raman imaging nanoparticle (termed here MPR nanoparticle) can accurately help delineate the margins of brain tumors in living mice both preoperatively and intraoperatively. The MPRs were detected by all three modalities with at least a picomolar sensitivity both in vitro and in living mice. Intravenous injection of MPRs into glioblastoma-bearing mice led to MPR accumulation and retention by the tumors, with no MPR accumulation in the surrounding healthy tissue, allowing for a noninvasive tumor delineation using all three modalities through the intact skull. Raman imaging allowed for guidance of intraoperative tumor resection, and a histological correlation validated that Raman imaging was accurately delineating the brain tumor margins. This new triple-modality-nanoparticle approach has promise for enabling more accurate brain tumor imaging and resection.

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A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle

We designed, fabricated and tested the laser optoacoustic imaging system for breast cancer detection LOIS-64, which fuses optical and acoustic imaging techniques in one modality by utilizing pulsed optical illumination and ultrawide-band ultrasonic detection of resulting optoacoustic OA signals. The system was designed to im- age a single breast slice in craniocaudal or mediolateral projection with an arc-shaped array of 64 ultrawide-band acoustic transducers. The system resolution on breast phantoms was at least 0.5 mm. The single-channel sensitivity of 1.66 mV/Pa was estimated to be suffi- cient for single-pulse imaging of 6t o 11 mm tumors through the whole imaging slice of the breast. The implemented signal processing using the wavelet transform allowed significant reduction of the low- frequency LF acoustic noise, allowed localization of the optoacous- tic signals from tumors, and enhanced the contrast and sharpened the boundaries of the optoacoustic images of the tumors. During the pre- liminary clinical studies on 27 patients, the LOIS-64 was able to visu- alize 18 out of 20 malignant lesions suspected from mammography and ultrasound images and confirmed by the biopsy performed after the optoacoustic tomography OAT procedure. © 2009 Society of Photo-

https://www.spiedigitallibrary.org/journals/Journal-of-Biomedical-Optics/volume-14/issue-2/024007/Laser-optoacoustic-imaging-system-for-detection-of-breast-cancer/10.1117/1.3086616.pdf

Laser optoacoustic imaging system for detection of breast cancer

A method of obtaining aliquots or samples from a liquid specimen collection container and an apparatus which automateally perforths those methods involves transferring a sample of liquid from a sealed non-deformingly expandable container containing gas and the liquid without contaminating the liquid remaining inside the container, and comprises (a) non-deformingly volumetrically expanding the sealed container sufficiently to reduce pressure therein below ambient pressure outside the container, (b) applying heat selectively to a locus on said enlarged container to non-invasively create a hole having a diameter effective to equilibrate the pressure inside the container with said ambient pressure without loss of liquid from the container, and (c) non-deformingly volumetrically reducing the container to expel liquid from the container through the hole.

Liquid specimen transfer apparatus and method

Substantially moisture-proof, airtight dispensers (20,900) for both storing and dispensing several flattened articles such as diagnostic test strips is disclosed. The dispensers fits comfortably in a user's hand and can be configured to provide a test strip either by a squeezing motion or by flipping a trigger at the top of the dispenser, for example with the user's thumb. The dispensers are easy to manually operate and are thus well suited for diabetics suffering from nerve damage in their extremities and other complications resulting from the disease. When used with a separate meter (700), an integrated RFID tag can provide automated coding of the test strip information into the meter.

Dispenser for flattened articles

A handheld optoacoustic probe includes an ultrasound transducer array and optical fibers with a first end formed into a fiber bundle providing an input and a second, distal end providing an output. A light bar guide retains the distal end of the optical fibers on the same plane. One or more optical windows may be associated with, and spaced from the light bar guide so as to prevent contact between a coupling agent and the distal ends of the optical fibers, thus mitigating a potential acoustic effect of the coupling agent in response to light emitting from the fibers. A silicon rubber acoustic lens doped with TiO2 may be provided, with a reflective metal surrounding the outer surface of the acoustic lens. A handheld probe shell houses the light bar guide, the ultrasound transducer array, and the acoustic lens.

Handheld optoacoustic probe

A method for dispensing a sample of liquid from a sealed thermoplastic container which includes both a volumetrically flexible chamber holding the liquid and also a plurality of spaced axially vertical nozzles on the container underside, the nozzles having an inlet in fluid communication with the chamber. The container is first manipulated to increase the volume of the chamber, rotated from a right side up position to an upside down position, and after the two preceding operations an axial opening is non-invasively created in the nozzle while the container is upside down without decreasing the volume of the chamber. The container is then rotated from the upside down position to a right side up position without decreasing the volume of the chamber, manipulated to decrease the volume of the chamber and expel a sample of the liquid from the chamber through the nozzle opening, then rotated to an upside down position and the opening in the nozzle is closed by melting and clamping it closed.

Thomas G. Miller

Papers

Laser optoacoustic imaging system for detection of breast cancer

Liquid specimen transfer apparatus and method

Dispenser for flattened articles

Handheld optoacoustic probe

Liquid container sample transfer method and apparatus