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and the extent of attenuation depends on wavelength. The measured spectral signature of photoabsorbers inside tissue may therefore differ from the absorption spectrum of the same molecule measured inside the cuvette of a spectrophotometer. This discrepancy, termed "spectral coloring", depends on the number and types of photoabsorbers in the propagation path. Spectral coloring poses a challenge to spectral unmixing, which requires accurate knowledge of the absorption spectrum. Moreover, optoacoustic imaging, with a resolution in the range of 1-100 μm, cannot resolve individual photoabsorbing molecules. As a result, the spectral response of the photoabsorber of interest is a linear combination of the spectral responses of background tissue constituents, such as oxy- and deoxy-hemoglobin,
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absorbed by the sample is converted to heat; the resulting temperature rise, on the order of milli-Kelvins, leads to thermo-elastic expansion of the sample. This creates a pressure wave in the form of a broadband ultrasound wave. The ultrasound waves emitted by the sample are detected by transducers positioned near the sample, usually at multiple positions around it. The amplitude of the pressure wave provides information about the local absorption and propagation of energy in the sample, while the time interval between the illumination pulse and arrival of the ultrasound wave at the detector provides information about the distance between the detector and photoecho source. Optoacoustic data collected over time and at multiple positions around the sample are processed using
264:
analog-to-digital converters allow simultaneous data collection over 512 parallel elements, substantially shortening the amount of time needed to acquire a tomographic dataset, even to the point of allowing video-rate imaging. In addition, lasers have been developed that allow switching between wavelengths within 20 ms, enabling video-rate MSOT. Video-rate imaging not only reduces motion artifacts, but also allows in vivo study of biological processes, even in hand-held mode. It also gives the operator real-time feedback essential for orientation and fast localization of areas of interest.
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typically uses detectors operating in the frequency range from 0.1 to 10 MHz, allowing imaging depths of approximately 1–5 cm and resolution of 0.1–1 mm. Illumination light wavelengths are typically chosen from the near-IR region of the spectrum and spread over the sample to allow deep penetration. Images are then generated using computed tomography. Such macroscopy is useful for animal and human imaging to analyze tissue anatomy, physiology and response to drugs. Regions of interest are approximately 30–50 cm, and resolution of 200-300 microns is typical.
469:, such as the fluorochromes indocyanine green and methylene blue, are non-specific, approved for clinical use, and suitable for perfusion imaging. They typically have low quantum yield, so they convert a large portion of absorbed energy into heat and thus photoechoes. Since these dyes can be imaged based on optoacoustics and fluorescence, the two types of microscopies can be used to complement and verify each other. In fact, organic dyes are generally well characterized because of their widespread use in fluorescence imaging. Photosensitizers, already in clinical use for
216:, such as oxy- and deoxy-hemoglobin, myoglobin, melanin or exogenous photoabsorbers. The wavelengths of light used to illuminate samples in MSOT are selected based on the absorption characteristics of the target photoabsorbers. To resolve the individual photoabsorbers, images obtained at multiple wavelengths must be further processed using subtraction or spectral unmixing techniques. Background in images can be reduced by exploiting differences in time (baseline subtraction) and in absorption spectra of the various photoabsorbers (spectral unmixing).
79:(imaging probes, nanoparticles). Computational techniques such as spectral unmixing deconvolute the ultrasound waves emitted by these different absorbers, allowing each emitter to be visualized separately in the target tissue. In this way, MSOT can allow visualization of hemoglobin concentration and tissue oxygenation or hypoxia. Unlike other optical imaging methods, MSOT is unaffected by photon scattering and thus can provide high-resolution optical images deep inside biological tissues.
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size and spectral unmixing method. As imaging depth increases, light and ultrasound attenuation together reduce the optoacoustic signal and therefore the overall detection sensitivity. Ultrasound attenuation is frequency-dependent: higher frequencies are attenuated faster with increasing depth. Selecting ultrasound detectors that are most sensitive at the appropriate frequency can improve sensitivity at the target imaging depth, but at the cost of spatial resolution.
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lower concentration does not provide strong signal over the background signal from blood. Different structures in the mouse brain are indicated: sv, supraorbital veins; icv, inferior cerebral vein; sss, superior sagittal sinus; cs, confluence of sinuses; ts, transverse sinus. (c) Time series of maximal-intensity projections following multi-wavelength illumination after injection of 10 nmol indocyanine green. Inflow of the contrast agent can be followed in real time.
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sentinel lymph node (in color), overlaid on a background image of tissue illuminated at a single wavelength. Each image came from a different patient. (c) MSOT imaging of melanin (in color) overlaid on a background image of tissue. The first image shows a patient without melanoma metastasis. The second image shows a patient with melanoma metastasis inside the sentinel lymph node. In both cases, strong melanin signal from the skin can be seen
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hemoglobin oxygenation that was not detectable by ultrasound. Moreover, optoacoustic endoscopy can detect the exogenous dye Evans blue after injection into the lymphatic system. Ongoing technological progress is expected to allow optoacoustic imaging of the gastrointestinal tract in humans in the near future, which may allow three-dimensional analysis of suspicious lesions, providing more complete information than white light endoscopy.
242:
using focused ultrasound detectors to limit ultrasound detection to a two-dimensional plane in the illuminated volume. The result is a series of two-dimensional, cross-sectional images, which can be collected in real time and can show quite high in-plane resolution if detector elements are packed at high density around the image plane. Translating the detector along the third dimension then allows volumetric scanning.
437:
oxygenation states of hemoglobin, enabling label-free assessment of tissue oxygenation and hypoxia, both of which are useful parameters in many pathologies and functional studies. Hemoglobin-based imaging to resolve vascular abnormalities and oxygenation status may be useful for various applications, including perfusion imaging, inflammation imaging, and tumor detection and characterization.
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allowed to accumulate inside the sentinel lymph node. MSOT may provide a non-radioactive, non-invasive alternative for examination of the metastatic status of the sentinel lymph node. Initial studies have shown that MSOT can detect sentinel lymph nodes based on indocyanine green (ICG) accumulation after injection in the tumor, as well as melanoma metastasis inside the lymph nodes.
490:, and iron-oxide particles have been used for optoacoustic imaging in animals. Gold nanoparticles generate strong optoacoustic signals due to plasmon resonance, and their absorption spectrum can be tuned by modifying their shape. Some iron oxide nanoparticles, such as SPIO, have already been approved for the clinic as MRI contrast agents.
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from the visible and near-IR regions of the spectrum. Images are generated using computed tomography. Such mesoscopy can analyze morphology and biological processes such as inflammation in greater detail than macroscopy, revealing, for example, microvasculature networks in skin and epithelial tissues or the microenvironment within a
630:
Fig. 5: MSOT for determination of the metastatic status of sentinel lymph nodes in melanoma patients. (A) Indocyanine green (ICG) is injected and accumulates inside the sentinel lymph node, which is detected using a hand-held two-dimensional MSOT device. (b) MSOT images of the ICG accumulating in the
496:
combine a dye or nanoparticle with a targeting ligand to provide MSOT contrast at specific tissues or in the presence of specific cellular or molecular processes. Such agents have been used in MSOT imaging of integrins within tumors in animals. Targeted agents can also be activatable, such that their
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have been developed, or are under development, for optoacoustics. These contrast agents should have an absorption spectrum different from that of endogenous tissue absorbers, so that they can be separated from other background absorbers using spectral unmixing. Different classes of exogenous contrast
331:
Ultrasound detectors have been developed that collect bandwidths of 10-200 MHz or wider, which allows unprecedented mesoscopy at tissue depths of 0.1–1 cm with resolution that can exceed 10 microns even at depths of several millimeters. Illumination light is typically unfocused and selected
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Optoacoustic (photoacoustic) imaging is intrinsically a three-dimensional imaging method, since photoechoes (optoacoustic waves) propagate in all three spatial dimensions. Optimal tomographic imaging is therefore achieved by recording time-resolved pressure waves along a closed surface volumetrically
542:
Because of its ability to provide spatial and spectral resolution in real time on multiple scales, optoacoustic imaging in general and MSOT in particular are likely to play an important role in clinical imaging and management of cancer, cardiovascular disease and inflammation. MSOT presents numerous
443:
is another important endogenous absorber; it absorbs over a broad range of wavelengths in the visible and near-IR range, with absorption decreasing at longer wavelengths. Optoacoustic imaging of melanin has been used to assess the depth of melanoma ingrowth inside epithelial tissue and to assess the
415:
Earlier calculations predicted that MSOT should be able to detect concentrations of organic fluorochromes as low as 5 nM. These calculations did not properly account for frequency-dependent attenuation of ultrasound in tissue or for the requirements of spectral unmixing. Experimental results suggest
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A large amount of data must be collected and processed for truly three-dimensional imaging, necessitating a large detector array, long scanning times, and heavy computational burden. To reduce these requirements, the three-dimensional problem is often simplified to a quasi-two-dimensional problem by
224:
MSOT has the potential to provide multi-parametric information involving the three spatial dimensions (x, y, z), time, optical wavelength spectrum and ultrasound frequency range. It has therefore been described as a six-dimensional modality. This dimensionality has been made possible by key advances
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waves generated by thermo-elastic expansion of a sample (e.g. tissue) after absorption of transient electromagnetic energy. Typically, the sample is illuminated with light pulses in the nanosecond range, although intensity-modulated light can also be used. At least some of the electromagnetic energy
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Optoacoustic imaging in general and MSOT in particular may address a number of challenges for surgical procedures by providing real-time visualization below the tissue surface. In particular, optoacoustic imaging can provide immediate information on the perfusion status of tissues based on analysis
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Light delivery and ultrasound detection can be miniaturized to create optoacoustic endoscopy systems for gastrointestinal applications. A system combining MSOT and ultrasound endoscopy has been used to image the esophagus and colon in rats and rabbits. The MSOT images revealed vascular features and
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Optoacoustic mesoscopy is suitable for imaging skin lesions. Studies in preclinical models have imaged subcutaneous lesions and their vascular networks and demonstrated the potential to reveal lesion details such as depth, vascular morphology, oxygenation and melanin content. Combining optoacoustic
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Fig. 4: MSOT of human vasculature. The handheld MSOT probe shown here to measure photoechoes from hemoglobin, allows more sensitive detection of small blood vessels than
Doppler ultrasound already in the clinic. Different structures are indicated: ADP, dorsalis pedis artery; ATP, tibialis posterior
447:
MSOT can detect several other endogenous tissue absorbers, as long as the correct wavelength range is used to illuminate the sample. Lipids can be imaged at near-IR wavelengths, with the absorption peak occurring at 930 nm. Water absorbs strongly at near-IR wavelengths longer than 900 nm,
386:
MSOT provides anatomical, dynamic and molecular information, but quantifying the features of MSOT images is not straightforward because constituents of the target tissue absorb and scatter the illuminating light. As a result, the illuminating light is attenuated as one moves deeper into the tissue,
327:
Photoechoes show an ultra-wide frequency profile, which is determined by the pulse width of the illuminating pulse and the size of the object. Ultimately, though, the frequencies that can be collected and processed for image reconstruction are determined by the ultrasound detector. Macroscopic MSOT
318:
as an intrinsic oxygen sensor, MSOT is the only method available that can provide high-resolution images of tissue oxygenation without the need for exogenous labels. At the same time, MSOT can image additional endogenous photoabsorbers such as lipids and water, as well as exogenous contrast agents.
313:
Through spectral unmixing and other techniques, MSOT data can be used to generate separate images based on the contrast provided by different photoabsorbers. In other words, a single MSOT data collection run provides separate images showing the distribution of oxy- or deoxy-hemoglobin. These images
289:
A key strength of MSOT is its ability to resolve the photoechoes obtained in response to excitation with different wavelengths of illuminating light. Since the photoechoes depend on the optical absorption characteristics of molecules within the target tissue (or added to the tissue), MSOT can image
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Therefore, the sensitivity of MSOT depends on the contrast agent used, its distribution and accumulation in the target tissue, and its resistance to photobleaching by the illuminating light. Sensitivity also depends on the ultrasound detector employed, the amount of light energy applied, the voxel
407:
are optimized for fluorescence emission and are sub-optimal for optoacoustic detection, because after absorbing the illuminating energy, they tend to emit fluorescence rather than convert it to heat and generate a photoecho. Dyes with higher absorption cross-sections generate stronger optoacoustic
279:
perfusion in vivo. (a) Layout of the experimental set-up. (b) Maximal-intensity projections along the axial direction following single-wavelength illumination before (upper) and after injection of two concentrations of contrast agent (10nmol in the middle and 50 nmol lower), indocyanine green. The
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Early optoacoustic imaging involved scanning a single ultrasound detector along one or two dimensions, resulting in acquisition times of several seconds, minutes or longer. This made the technique impractical for in vivo animal imaging or clinical use. Technological advances in detector arrays and
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Optoacoustic imaging in general, and MSOT in particular, have been applied to various analyses of animal models, including imaging of organs, pathology, functional processes and bio-distribution. This range of applications demonstrates the flexibility of MSOT, which reflects the range of contrast
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to produce images of the distribution of photoabsorbers in the sample. Data collected after illumination at single wavelengths allow imaging of the distribution of photoabsorbers that share similar absorption characteristics at the given wavelength. Data collected after illumination with multiple
533:
pupae and adult zebrafish, and mCherry has been imaged in tumor cells in the mouse brain. This transgenic approach is not limited to fluorescent proteins: infecting tissue with a vaccinia virus carrying the tyrosinase gene allows in situ production of melanin, which generates strong optoacoustic
192:
Fig. 1: Operational capabilities of MSOT. Hybrid image showing an optical micrograph of part of a mouse kidney cross-section (gray), overlaid with the distribution of an exogenous fluorescent agent imaged using MSOT (right). Distribution of oxy-hemoglobin (red) and deoxy-hemoglobin (blue) in the
617:
Melanoma metastasizes early into regional lymph nodes, so excision and analysis of so-called sentinel lymph nodes is important for treatment planning and prognosis assessment. To identify the sentinel lymph node for excision, a gamma-emitting radiotracer is injected inside the primary tumor and
572:
The hemoglobin distribution in carotid arteries of healthy humans has recently been imaged in real time using a hand-held device similar to diagnostic ultrasound systems currently in the clinic. The ability to image blood vessels in hands and feet may be useful for assessing peripheral vascular
339:
The possibility of applying optoacoustics to the microscopic regime has been suggested. This involves scanning focused light on the tissue surface. The imaging depth (typically <1 mm) and quality of the resulting image are limited by optical diffraction and scattering, not by ultrasound
563:
and the low specificity of ultrasound imaging. MSOT may miss fewer malignancies in dense breast tissue than these conventional modalities because optoacoustic contrast is unaffected by breast density. MSOT studies of breast cancer typically focus on detecting the increased vascular density and
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is the dominant absorber of light in the visible and near-IR part of the optical spectrum and is commonly used for optoacoustic imaging. Endogenous contrast provided by hemoglobin allows sensitive imaging of vascular anatomy at various scales. Using MSOT further allows the distinction between
87:
MSOT has been described as a 6-dimensional (6-parametric) method, in which the three geometrical dimensions (x, y, z) are complemented by time, illumination wavelengths and band of ultrasound frequencies detected. MSOT can measure over time, allowing longitudinal studies of dynamic processes.
1212:
J. Stritzker, L. Kirscher, M. Scadeng, N.C. Deliolanis, S. Morscher, P. Symvoulidis, K. Schaefer, Q. Zhang, L. Buckel, M. Hess, U. Donat, W.G. Bradley, V. Ntziachristos, A.A. Szalay, "Vaccinia virus-mediated melanin production allows MR and optoacoustic deep tissue imaging and laser-induced
1038:
I. Stoffels, S. Morscher, I. Helfrich, U. Hillen, J. Lehy, N.C. Burton, T.C.P. Sardella, J. Claussen, T.D. Poeppel, H.S. Bachmann, A. Roesch, K. Griewank, D. Schadendorf, M. Gunzer, J. Klode, "Metastatic status of sentinel lymph nodes in melanoma determined noninvasively with multispectral
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an in vivo detection sensitivity of 0.1-1 μM for organic dyes with a minimum detectable optical absorption coefficient of 0.1–1 cm, such as indocyanine green and Alexa fluochromes. Advanced spectral unmixing methods based on statistical detection schemes can improve MSOT sensitivity.
958:
M. Heijblom, D. Piras, M. Brinkhuis, J.C.G. van Hespen, F.M. van den Engh, M. van der Schaaf, J.M. Klaase, T.G. van
Leeuwen, W. Steenbergen, S. Manohar, "Photoacoustic image patterns of breast carcinoma and comparisons with Magnetic Resonance Imaging and vascular stained histopathology",
924:
Q. Ruan, L. Xi, S.L. Boye, S. Han, Z.J. Chen, W.W. Hauswirth, A.S. Lewin, M.E. Boulton, B.K. Law, W.G. Jiang, H. Jiang, J. Cai, "Development of an anti-angiogenic therapeutic model combining scAAV2-delivered siRNAs and noninvasive photoacoustic imaging of tumor vasculature development",
179:
This term denotes images formed by combining raw measurements from multiple points around the specimen in a mathematical inversion scheme. This process is analogous to x-ray computed tomography, except that tomographic mathematical models describe light and sound propagation in tissues.
1202:
A.P. Jathoul, J. Laufer, O. Ogunlade, B. Treeby, B. Cox, E. Zhang, P. Johnson, A.R. Pizzey, B. Philip, T. Marafioti, M.F. Lythgoe, R.B. Pedley, M.A. Pule, P. Beard, Deep in vivo photoacoustic imaging of mammalian tissues using a tyrosinase-based genetic reporter, Nat Photon 9 (2015)
253:
Fig. 2: Volumetric optoacoustic imaging and comparison with reflection-mode ultrasound computed tomography. Cross-sectional tomographic ultrasound (right) and optoacoustic (middle) whole-body image stacks of a living mouse. Histology cross-sections of the tissue shown on the
377:, which exploits the multi-spectral capability of MSOT. This mode has been used to visualize tissue oxygenation, reporter genes, fluorescent proteins and various exogenous agents (e.g. fluorescent dyes, nanoparticles, target-specific agents) in laboratory animals and humans.
425:
agents available. Practically every molecule that absorbs light and converts it to a pressure wave has the potential to be detected with optoacoustics. Contrast agents absorbing light in the near-IR are particularly attractive, because they enable imaging at greater depth.
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imaging, which can be performed using a single wavelength of illuminating light and at multiple scales. This mode has been used to visualize various tissue structures and organs in laboratory animals and humans, including vasculature, kidney, heart, liver, brain and
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advantages over other radiology modalities because of its ability to resolve oxygenated and deoxygenated hemoglobin, its compatibility with a broad array of exogenous contrast agents, its scalability and its ability to image rapidly even below the tissue surface.
477:
offer potential advantages over organic dyes because of their ability to produce stronger photoechoes and their lower photosensitivity. One disadvantage is that they must be approved individually for human use because their safety has not been well established.
609:, improving our ability to detect atherosclerosis and stent-related biomarkers. Optoacoustic imaging is likely to be well suited to this application, since it can detect lipids, neovasculature, hemoglobin oxygenation and contrast agents that mark inflammation.
395:, which further complicates unmixing. Recently, eigenspectra MSOT has been developed to model more accurately the spectral responses of different photoabsorbers in three-dimensional tissue. This may help improve spectral unmixing and therefore image quality.
519:) allow imaging deep inside tissues. MSOT based on in situ expression of fluorescent proteins can take advantage of tissue- and development-specific promoters, allowing imaging of specific parts of an organism at specific stages of development. For example,
1496:
A. De La Zerda, C. Zavaleta, S. Keren, S. Vaithilingam, S. Bodapati, Z. Liu, J. Levi, B.R. Smith, T.-J. Ma, O. Oralkan, Z. Cheng, X. Chen, H. Dai, B.T. Khuri-Yakub, S.S. Gambhir, "Carbon nanotubes as photoacoustic molecular imaging agents in living mice",
1619:
M. Heijblom, D. Piras, W. Xia, J.C.G. van Hespen, J.M. Klaase, F.M. van den Engh, T.G. van
Leeuwen, W. Steenbergen, S. Manohar, "Visualizing breast cancer using the Twente photoacoustic mammoscope: What do we learn from twelve new patient measurements?",
844:
N.C. Burton, M. Patel, S. Morscher, W.H.P. Driessen, J. Claussen, N. Beziere, T. Jetzfellner, A. Taruttis, D. Razansky, B. Bednar, V. Ntziachristos, "Multispectral Opto-acoustic
Tomography (MSOT) of the Brain and Glioblastoma Characterization",
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C. Kim, K.H. Song, F. Gao, L.V. Wang, "Sentinel Lymph Nodes and
Lymphatic Vessels: Noninvasive Dual-Modality in Vivo Mapping by Using Indocyanine Green in Rats—Volumetric Spectroscopic Photoacoustic Imaging and Planar Fluorescence Imaging",
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J. Levi, S.-R. Kothapalli, S. Bohndiek, J.-K. Yoon, A. Dragulescu-Andrasi, C. Nielsen, A. Tisma, S. Bodapati, G. Gowrishankar, X. Yan, C. Chan, D. Starcevic, S.S. Gambhir, "Molecular
Photoacoustic Imaging of Follicular Thyroid Carcinoma",
1383:
E.I. Galanzha, E.V. Shashkov, P.M. Spring, J.Y. Suen, V.P. Zharov, "In vivo, Noninvasive, Label-Free
Detection and Eradication of Circulating Metastatic Melanoma Cells Using Two-Color Photoacoustic Flow Cytometry with a Diode Laser",
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A. Chekkoury, J. Gateau, W. Driessen, P. Symvoulidis, N. Bézière, A. Feuchtinger, A. Walch, V. Ntziachristos, Optical mesoscopy without the scatter: broadband multispectral optoacoustic mesoscopy, Biomedical Optics
Express 6 (2015)
105:
resolution is also possible using multi-spectral optoacoustics. Like optical microscopy, they use focused light to form images and offers fundamentally the same capabilities (submicrometer resolution, <1mm penetration depth).
759:
W. Assmann, S. Kellnberger, S. Reinhardt, S. Lehrack, A. Edlich, P.G. Thirolf, M. Moser, G. Dollinger, M. Omar, V. Ntziachristos, K. Parodi, "Ionoacoustic characterization of the proton Bragg peak with submillimeter accuracy",
88:
Illumination wavelengths in MSOT can cover the entire spectrum from ultraviolet (UV) to infrared (IR). The wavelength defines the photoabsorbers that can be seen and the imaging depth. High-energy ion beams and energy in the
1743:
J. Gateau, M.Á.A. Caballero, A. Dima, V. Ntziachristos, Three-dimensional optoacoustic tomography using a conventional ultrasound linear detector array: Whole-body tomographic system for small animals, Med. Phys. 40 (2013)
55:. MSOT illuminates tissue with light of transient energy, typically light pulses lasting 1-100 nanoseconds. The tissue absorbs the light pulses, and as a result undergoes thermo-elastic expansion, a phenomenon known as the
92:
range have also been used. The choice of ultrasound frequency band defines resolution and overall size range of the objects that can be resolved. This choice of frequency band dictates whether the imaging will be in the
988:
S. Manohar, S.E. Vaartjes, J.C.G.v. Hespen, J.M. Klaase, F.M.v.d. Engh, W. Steenbergen, T.G.v. Leeuwen, "Initial results of in vivo non-invasive cancer imaging in the human breast using near-infrared photoacoustics",
1231:
S. Tzoumas, A. Nunes, I. Olefir, S. Stangl, P. Symvoulidis, S. Glasl, C. Bayer, G. Multhoff, V. Ntziachristos, "Eigenspectra optoacoustic tomography achieves quantitative blood oxygenation imaging deep in tissues",
884:
S. Gottschalk, T. Felix Fehm, X. Luís Deán-Ben, D. Razansky, "Noninvasive real-time visualization of multiple cerebral hemodynamic parameters in whole mouse brains using five-dimensional optoacoustic tomography",
63:. This expansion gives rise to ultrasound waves (photoechoes) that are detected and formed into an image. Image formation can be done by means of hardware (e.g. acoustic focusing or optical focusing) or computed
1068:
B. Zabihian, J. Weingast, M. Liu, E. Zhang, P. Beard, H. Pehamberger, W. Drexler, B. Hermann, "In vivo dual-modality photoacoustic and optical coherence tomography imaging of human dermatological pathologies",
641:
of hemoglobin dynamics and oxygenation. This may, for example, detect areas at high risk of anastomotic leakage under ischemic conditions in the colon or esophagus, allowing preventive measures to be taken.
564:
correspondingly high hemoglobin concentration thought to occur in and around tumors. The flexibility of MSOT may also allow imaging of other tissue and cancer biomarkers not detectable with current methods.
340:
diffraction. In other words, optoacoustic microscopy has the same limitations as conventional optical microscopy. Together, however, the two microscopies can provide more information than either on its own.
234:
surrounding the target tissue. Typically, three-dimensional imaging systems achieve this by scanning a single ultrasound sensor around the sample, or by using one-dimensional or two-dimensional ultrasound
825:
B. Wang, E. Yantsen, T. Larson, A.B. Karpiouk, S. Sethuraman, J.L. Su, K. Sokolov, S.Y. Emelianov, "Plasmonic
Intravascular Photoacoustic Imaging for Detection of Macrophages in Atherosclerotic Plaques",
1592:
A. Taruttis, S. Morscher, N.C. Burton, D. Razansky, V. Ntziachristos, "Fast
Multispectral Optoacoustic Tomography (MSOT) for Dynamic Imaging of Pharmacokinetics and Biodistribution in Multiple Organs",
1456:
C.J.H. Ho, G. Balasundaram, W. Driessen, R. McLaren, C.L. Wong, U.S. Dinish, A.B.E. Attia, V. Ntziachristos, M. Olivo, "Multifunctional Photosensitizer-Based Contrast Agents for Photoacoustic Imaging",
551:
MSOT can track the fate of administered agents in blood circulation, allowing real-time, in vivo analysis of pharmacokinetics. This may reduce the numbers of animals needed in biomedical research.
1523:
M.L. Li, J.T. Oh, X. Xie, G. Ku, W. Wang, C. Li, G. Lungu, G. Stoica, L.V. Wang, "Simultaneous Molecular and Hypoxia Imaging of Brain Tumors In Vivo Using Spectroscopic Photoacoustic Tomography",
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MSOT can detect exogenous contrast agents up to a depth of 5 cm in tissue if the overlaying tissue is sufficiently compressed. It has been evaluated on 500 removed lymph nodes to check for
812:
A. Taruttis, M. Wildgruber, K. Kosanke, N. Beziere, K. Licha, R. Haag, M. Aichler, A. Walch, E. Rummeny, V. Ntziachristos, "Multispectral optoacoustic tomography of myocardial infarction",
1659:
J.-M. Yang, C. Favazza, R. Chen, J. Yao, X. Cai, K. Maslov, Q. Zhou, K.K. Shung, L.V. Wang, "Simultaneous functional photoacoustic and ultrasonic endoscopy of internal organs in vivo",
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imaged, making it a multi-spectral method. Typically, MSOT is used to generate three images: one anatomical image at a single wavelength, one functional image resolving oxy- and deoxy-
140:
concentrations, and a third image resolving additional target photoabsorber(s). These additional photoabsorbers include melanin, fat, water and other endogenous or exogenous agents.
1470:
M. Eghtedari, A. Oraevsky, J.A. Copland, N.A. Kotov, A. Conjusteau, M. Motamedi, "High Sensitivity of In Vivo Detection of Gold Nanorods Using a Laser Optoacoustic Imaging System",
1751:
D. Soliman, G.J. Tserevelakis, M. Omar, V. Ntziachristos, Combining microscopy with mesoscopy using optical and optoacoustic label-free modes, Scientific Reports 5 (2015) 12902.
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E. Mercep, N.C. Burton, J. Claussen, D. Razansky, Whole-body live mouse imaging by hybrid reflection-mode ultrasound and optoacoustic tomography, Opt Lett 40 (2015) 4643–4646.
1606:
S.A. Ermilov, T. Khamapirad, A. Conjusteau, M.H. Leonard, R. Lacewell, K. Mehta, T. Miller, A.A. Oraevsky, "Laser optoacoustic imaging system for detection of breast cancer",
1553:
D. Razansky, M. Distel, C. Vinegoni, R. Ma, N. Perrimon, R.W. Koester, V. Ntziachristos, "Multispectral opto-acoustic tomography of deep-seated fluorescent proteins in vivo",
1007:
A. Taruttis, A.C. Timmermans, P.C. Wouters, M. Kacprowicz, G.M. van Dam, V. Ntziachristos, "Optoacoustic Imaging of Human Vasculature: Feasibility by Using a Handheld Probe",
871:
L. Xiang, L. Ji, T. Zhang, B. Wang, J. Yang, Q. Zhang, M.S. Jiang, J. Zhou, P.R. Carney, H. Jiang, "Noninvasive real time tomographic imaging of epileptic foci and networks",
310:. Transfecting target tissue with reporter genes to express contrast agents in situ has also been reported, such as transfection with the tyrosinase gene to produce melanin.
367:, which can be performed at video rates to reveal changes in tissue contrast caused by hemodynamics, motion such as vessel pulsation, and uptake of drugs (pharmacodynamics).
1055:
M. Schwarz, A. Buehler, J. Aguirre, V. Ntziachristos, "Three-dimensional multispectral optoacoustic mesoscopy reveals melanin and blood oxygenation in human skin in vivo",
306:
and water. Several exogenous contrast agents have also been used in MSOT, including some common histology dyes, fluorescent dyes, novel metal-based agents and non-metallic
858:
J. Yao, J. Xia, K.I. Maslov, M. Nasiriavanaki, V. Tsytsarev, A.V. Demchenko, L.V. Wang, "Noninvasive photoacoustic computed tomography of mouse brain metabolism in vivo",
1579:
R.J. Paproski, A. Heinmiller, K. Wachowicz, R.J. Zemp, "Multi-wavelength photoacoustic imaging of inducible tyrosinase reporter gene expression in xenograft tumors",
898:
E. Herzog, A. Taruttis, N. Beziere, A.A. Lutich, D. Razansky, V. Ntziachristos, "Optical Imaging of Cancer Heterogeneity with Multispectral Optoacoustic Tomography",
911:
J. Laufer, P. Johnson, E. Zhang, B. Treeby, B. Cox, B. Pedley, P. Beard, "In vivo preclinical photoacoustic imaging of tumor vasculature development and therapy",
225:
in laser source and detector technology, computed tomography and unmixing techniques. The capabilities and challenges of each MSOT dimension are described below.
1483:
K.A. Homan, M. Souza, R. Truby, G.P. Luke, C. Green, E. Vreeland, S. Emelianov, "Silver Nanoplate Contrast Agents for in Vivo Molecular Photoacoustic Imaging",
1121:
H.P. Brecht, R. Su, M. Fronheiser, S.A. Ermilov, A. Conjusteau, A.A. Oraevsky, "Whole-body three-dimensional optoacoustic tomography system for small animals",
1344:
S. Tzoumas, A. Kravtsiv, Y. Gao, A. Buehler, V. Ntziachristos, "Statistical molecular target detection framework for multispectral optoacoustic tomography",
290:
the distributions of specific photoabsorbing molecules. The endogenous photoabsorbers most often imaged are oxy- and deoxy-hemoglobin, key players in oxygen
170:
are to optoacoustics what photon is to optics: optical methods rely on photons, whereas optoacoustic methods rely on photoechoes or photoacoustic responses.
1566:
A. Krumholz, D.M. Shcherbakova, J. Xia, L.V. Wang, V.V. Verkhusha, "Multicontrast photoacoustic in vivo imaging using near-infrared fluorescent proteins",
158:. Photoecho denotes the combination of light (Greek, Φως <phos>) and sound ( Ήχος <echos>) or reflection of sound Hχώ <echo>). The term
1331:
S. Tzoumas, N.C. Deliolanis, S. Morscher, V. Ntziachristos, "Unmixing Molecular Agents From Absorbing Tissue in Multispectral Optoacoustic Tomography",
972:
S. Manohar, A. Kharine, J.C.G. van Hespen, W. Steenbergen, T.G. van Leeuwen, "The Twente Photoacoustic Mammoscope: system overview and performance",
121:. The development of real-time hand-held imaging systems has enabled clinical use of MSOT for imaging the breast, vasculature, lymph nodes and skin.
1189:
E. Mercep, N.C. Burton, J. Claussen, D. Razansky, «Whole-body live mouse imaging by hybrid reflection-mode ultrasound and optoacoustic tomography»,
1020:
H.F. Zhang, K. Maslov, M.L. Li, G. Stoica, L.H.V. Wang, "In vivo volumetric imaging of subcutaneous microvasculature by photoacoustic microscopy",
71:
the sample with multiple wavelengths, allowing it to detect ultrasound waves emitted by different photoabsorbing molecules in the tissue, whether
1711:
S. Sethuraman, S.R. Aglyamov, J.H. Amirian, R.W. Smalling, S.Y. Emelianov, "Intravascular photoacoustic imaging using an IVUS imaging catheter",
1429:
D.-K. Yao, K. Maslov, K.K. Shung, Q. Zhou, L.V. Wang, "In vivo label-free photoacoustic microscopy of cell nuclei by excitation of DNA and RNA",
671:
403:
MSOT can resolve various optoacoustic moieties based on their absorption spectrum, including nanoparticles, dyes and fluorochromes. Most
1646:
C.P. Favazza, O. Jassim, L.A. Cornelius, L.V. Wang, "In vivo photoacoustic microscopy of human cutaneous microvasculature and a nevus",
1370:
H.F. Zhang, K. Maslov, G. Stoica, L.V. Wang, "Functional photoacoustic microscopy for high-resolution and noninvasive in vivo imaging",
1315:
D. Razansky, J. Baeten, V. Ntziachristos, "Sensitivity of molecular target detection by multispectral optoacoustic tomography (MSOT)",
1150:
X.L. Deán-Ben, D. Razansky, "Adding fifth dimension to optoacoustic imaging: volumetric time-resolved spectrally enriched tomography",
1698:
A.B. Karpiouk, B. Wang, S.Y. Emelianov, "Development of a catheter for combined intravascular ultrasound and photoacoustic imaging",
1289:
N. Beziere, V. Ntziachristos, "Optoacoustic Imaging of Naphthalocyanine: Potential for Contrast Enhancement and Therapy Monitoring",
497:
absorption spectrum changes as the result of a change in the microenvironment. For example, a contrast agent activatable by matrix
1108:
S. Kellnberger, N.C. Deliolanis, D. Queirós, G. Sergiadis, V. Ntziachristos, "In vivo frequency domain optoacoustic tomography",
623:
246:
268:
773:
D. Razansky, S. Kellnberger, V. Ntziachristos, "Near-field radiofrequency thermoacoustic tomography with impulse excitation",
1510:
A. Hellebust, R. Richards-Kortum, "Advances in molecular imaging: targeted optical contrast agents for cancer diagnostics",
185:
473:, can be detected using MSOT, allowing analysis of their pharmacokinetics and bio-distribution in vivo. Light-absorbing
1302:
R.A. Kruger, W.L. Kiser, D.R. Reinecke, G.A. Kruger, K.D. Miller, "Thermoacoustic molecular imaging of small animals",
1176:
D. Razansky, A. Buehler, V. Ntziachristos, "Volumetric real-time multispectral optoacoustic tomography of biomarkers",
1095:
P. Mohajerani, S. Kellnberger, V. Ntziachristos, "Frequency domain optoacoustic tomography using amplitude and phase",
1163:
A. Buehler, E. Herzog, D. Razansky, V. Ntziachristos, "Video rate optoacoustic tomography of mouse kidney perfusion",
1724:
B. Wang, J.L. Su, A.B. Karpiouk, K.V. Sokolov, R.W. Smalling, S.Y. Emelianov, "Intravascular Photoacoustic Imaging",
945:
A. Buehler, M. Kacprowicz, A. Taruttis, V. Ntziachristos, "Real-time handheld multispectral optoacoustic imaging",
208:
515:, can also be visualized using MSOT. Newly developed fluorescent proteins that absorb in the near-IR range (e.g.
512:
508:
448:
with a strong peak at 980 nm. Bilirubin and cytochromes can be imaged at blue wavelengths. UV absorption by
746:
A. Taruttis, V. Ntziachristos, "Advances in real-time multispectral optoacoustic imaging and its applications",
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666:
502:
444:
metastatic status of sentinel lymph nodes in melanoma patients. It can also detect circulating melanoma cells.
154:(Greek, ακουστικός) energy (or components) in a single modality, which distinguishes optoacoustic imaging from
1276:
B. Cox, J.G. Laufer, S.R. Arridge, P.C. Beard, "Quantitative spectroscopic photoacoustic imaging: a review",
1263:
G.J. Tserevelakis, D. Soliman, M. Omar, V. Ntziachristos, "Hybrid multiphoton and optoacoustic microscope",
529:
1134:
R.A. Kruger, R.B. Lam, D.R. Reinecke, S.P. Del Rio, R.P. Doyle, "Photoacoustic angiography of the breast",
1416:
A. Taruttis, G.M. van Dam, V. Ntziachristos, "Mesoscopic and macroscopic optoacoustic imaging of cancer",
676:
606:
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K. Stephan, H. Amir, R. Daniel, N. Vasilis, "Near-field thermoacoustic tomography of small animals",
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Several optoacoustic studies have aimed to improve on the poor sensitivity of X-ray mammography in
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336:. Regions of interest are approximately 50 mm, and resolution of 5-30 microns is typical.
1672:
J.-M. Yang, K. Maslov, H.-C. Yang, Q. Zhou, K.K. Shung, L.V. Wang, "Photoacoustic endoscopy",
498:
374:
30:
imaging technology that generates high-resolution optical images including biological tissues.
706:, D. Razansky, "Molecular imaging by means of multispectral optoacoustic tomography (MSOT)",
703:
1357:
V. Ntziachristos, "Going deeper than microscopy: the optical imaging frontier in biology",
605:
Miniaturized optoacoustic devices are also expected to offer interesting possibilities for
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461:
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132:
MSOT collects images at multiple wavelengths and resolves the spectral signatures in each
118:
67:(mathematical image formation). Unlike other types of optoacoustic imaging, MSOT involves
1633:
A. Dima, V. Ntziachristos, "Non-invasive carotid imaging using optoacoustic tomography",
799:
L.V. Wang, S. Hu, "Photoacoustic Tomography: In Vivo Imaging from Organelles to Organs",
97:
regime, involving resolution of 100-500 microns and penetration depth >10 mm, or
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can be merged to provide a complete picture of tissue oxygenation/hypoxia. By using
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range, involving resolution of 1-50 microns and penetration depth <10 mm.
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Imaging with different ultrasound frequency bands (macro-, meso- and microscopy)
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wavelengths allow specific distinction of photoabsorbers with different optical
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is also widely used, and it denotes the generation of acoustic energy by light.
102:
94:
505:) cleavage has been used to image MMP activity within thyroid tumors in mice.
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MSOT has now been used in a broad range of biological applications, including
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that are already widespread, powerful tools for biomedical research, such as
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76:
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L.V. Wang, "Multiscale photoacoustic microscopy and computed tomography",
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mesoscopy with exogenous agents may provide further useful information.
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IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control
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T.-J. Yoon, Y.-S. Cho, "Recent advances in photoacoustic endoscopy",
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43:), also known as functional photoacoustic tomography (fPAT), is an
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fluorescent proteins have been imaged in model organisms such as
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Possible use for biopsy-free detection of lymph node metastasis
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Examination of metastatic status of sentinel lymph nodes
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75:(oxygenated and deoxygenated hemoglobin, melanin) or
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47:that generates high-resolution optical images in
1082:P. Beard, "Biomedical photoacoustic imaging",
452:has also been exploited to image cell nuclei.
578:artery; MH, medial hallux; DH, distal hallux.
8:
1687:World journal of gastrointestinal endoscopy
353:MSOT can operate in three imaging modes:
687:
382:Challenges to MSOT-based quantification
37:Multi-spectral optoacoustic tomography
18:
146:This term denotes the combination of
22:Multispectral optoacoustic tomography
7:
1726:IEEE J. Sel. Topics Quantum Electron
672:Photoacoustic imaging in biomedicine
275:Fig. 3: Five-dimensional imaging of
14:
1152:Light: Science & Applications
193:tumor, imaged using MSOT (left).
1650:16 (2011) 016015-016015-016016.
1215:Proc. Natl. Acad. Sci. U. S. A.
202:MSOT detects photoechoes, i.e.
1041:Science Translational Medicine
259:Video-rate (real-time) imaging
1:
391:, water, lipids and unknown
887:J. Cereb. Blood Flow Metab.
547:Imaging of pharmacokinetics
344:Operational characteristics
1781:
1213:thermotherapy of cancer",
429:Endogenous contrast agents
365:functional/dynamic imaging
238:to parallelize detection.
209:tomographic reconstruction
513:green fluorescent protein
460:A multitude of exogenous
456:Exogenous contrast agents
420:Contrast and applications
1346:IEEE Trans. Med. Imaging
1333:IEEE Trans. Med. Imaging
667:Photoacoustic tomography
568:Vascular disease imaging
494:Targeted contrast agents
1525:Proceedings of the IEEE
1057:Journal of biophotonics
1039:optoacoustic imaging",
530:Drosophila melanogaster
517:red fluorescent protein
1637:20 (2012) 25044-25057.
1624:20 (2012) 11582-11597.
993:15 (2007) 12277-12285.
636:Intraoperative imaging
626:
285:Multi-spectral imaging
271:
249:
220:Operational dimensions
188:
1234:Nature Communications
1217:110 (2013) 3316-3320.
803:335 (2012) 1458-1462.
710:110 (2010) 2783-2794.
625:
607:intravascular imaging
601:Intravascular imaging
555:Breast cancer imaging
538:Emerging applications
270:
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187:
150:(Greek, oπτικός) and
1676:34 (2009) 1591-1593.
1541:19 (2013) 1494-1502.
1433:35 (2010) 4139-4141.
1420:75 (2015) 1548-1559.
1388:69 (2009) 7926-7934.
1267:39 (2014) 1819-1822.
1167:35 (2010) 2475-2477.
1138:37 (2010) 6096-6100.
1112:37 (2012) 3423-3425.
1024:14 (2006) 9317-9323.
976:50 (2005) 2543-2557.
949:38 (2013) 1404-1406.
777:37 (2010) 4602-4607.
677:Optoacoustic imaging
509:Fluorescent proteins
484:silver nanoparticles
471:photodynamic therapy
198:Operating principles
61:photoacoustic effect
1474:7 (2007) 1914-1918.
1447:255 (2010) 442-450.
1193:40 (2015)4643-4646.
1180:6 (2011) 1121-1129.
1073:6 (2015) 3163-3178.
929:332 (2013) 120-129.
902:263 (2012) 461-468.
830:9 (2009) 2212-2217.
561:dense breast tissue
1728:16 (2010) 588-599.
1715:54 (2007) 978-986.
1700:Rev. Sci. Instrum.
1568:Scientific Reports
1527:96 (2008) 481-489.
1459:Scientific Reports
1374:24 (2006) 848-851.
1319:36 (2009) 939-945.
1293:56 (2015) 323-328.
1071:Biomed Opt Express
961:Scientific Reports
889:35 (2015) 531-535.
875:66 (2013) 240-248.
862:64 (2013) 257-266.
849:65 (2013) 522-528.
764:42 (2015) 567-574.
627:
480:Gold nanoparticles
349:Modes of operation
272:
250:
229:Volumetric imaging
214:absorption spectra
189:
113:disease research,
53:biological tissues
45:imaging technology
16:Imaging technology
1689:5 (2013) 534-539.
1663:18 (2012) 1297-+.
1610:14 (2009) 024007.
1557:3 (2009) 412-417.
1539:Clin. Cancer Res.
1514:7 (2012) 429-445.
1501:3 (2008) 557-562.
1487:6 (2012) 641-650.
1361:7 (2010) 603-614.
1306:2 (2003) 113-123.
1304:Molecular imaging
1254:3 (2009) 503-509.
1125:14 (2009) 064007.
1099:2 (2014) 111-118.
1086:1 (2011) 602-631.
750:9 (2015) 219-227.
534:signal for MSOT.
499:metalloproteinase
375:molecular imaging
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130:Multi-spectral.
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816:1 (2013) 3-8.
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475:nanoparticles
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168:photoacoustic
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160:photoacoustic
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144:Optoacoustic.
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1622:Opt. Express
1621:
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1608:J Biomed Opt
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1512:Nanomedicine
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1178:Nat. Protoc.
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1022:Opt. Express
1021:
1016:
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991:Opt. Express
990:
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927:Cancer Lett.
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657:metastasis.
648:
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629:
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583:Skin imaging
576:
575:
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558:
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541:
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467:Organic dyes
459:
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115:neuroimaging
108:
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69:illuminating
57:optoacoustic
51:, including
40:
36:
35:
1418:Cancer Res.
1386:Cancer Res.
1372:Nat Biotech
399:Sensitivity
393:metabolites
277:mouse brain
103:Microscopic
95:macroscopic
83:Description
1748:3134–3148.
1702:81 (2010).
1674:Opt. Lett.
1472:Nano Lett.
1431:Opt. Lett.
1317:Med. Phys.
1280:17 (2012).
1265:Opt. Lett.
1165:Opt. Lett.
1136:Med. Phys.
1110:Opt. Lett.
947:Opt. Lett.
915:17 (2012).
873:Neuroimage
860:Neuroimage
847:Neuroimage
828:Nano Lett.
775:Med. Phys.
762:Med. Phys.
748:Nat Photon
708:Chem. Rev.
683:References
434:Hemoglobin
371:biological
358:anatomical
316:hemoglobin
292:metabolism
204:ultrasound
175:Tomography
138:hemoglobin
99:mesoscopic
73:endogenous
65:tomography
1661:Nat. Med.
1597:7 (2012).
1445:Radiology
1191:Opt Lett.
1154:3 (2014).
1043:7 (2015).
1009:Radiology
900:Radiology
592:Endoscopy
573:disease.
488:nanotubes
486:, carbon
408:signals.
296:myoglobin
164:Photoecho
125:Etymology
77:exogenous
1759:Category
1595:PLoS ONE
1499:Nat Nano
1485:ACS Nano
1359:Nat Meth
1203:239-246.
661:See also
655:melanoma
152:acoustic
1744:013302.
1581:Sci Rep
801:Science
651:melanin
525:mCherry
441:Melanin
389:melanin
361:muscle.
304:melanin
148:optical
27:Purpose
300:lipids
334:tumor
254:left.
134:voxel
523:and
521:eGFP
166:and
117:and
41:MSOT
503:MMP
450:DNA
59:or
1761::
1546:^
1393:^
1324:^
1241:^
1222:^
1143:^
1048:^
1029:^
998:^
981:^
934:^
835:^
715:^
690:^
482:,
373:/
302:,
298:,
294:,
501:(
177:.
39:(
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