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95-470: 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. Illumination wavelengths in MSOT can cover the entire spectrum from ultraviolet (UV) to infrared (IR). The wavelength defines

190-449: A broad array of exogenous contrast agents, its scalability and its ability to image rapidly even below the tissue surface. 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. Several optoacoustic studies have aimed to improve on the poor sensitivity of X-ray mammography in dense breast tissue and

285-407: A change in the microenvironment. For example, a contrast agent activatable by matrix metalloproteinase ( MMP ) cleavage has been used to image MMP activity within thyroid tumors in mice. Fluorescent proteins that are already widespread, powerful tools for biomedical research, such as green fluorescent protein , can also be visualized using MSOT. Newly developed fluorescent proteins that absorb in

380-399: 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 melanin as a sign of melanoma metastasis. Radiofrequency Radio frequency ( RF ) is the oscillation rate of an alternating electric current or voltage or of a magnetic , electric or electromagnetic field or mechanical system in

475-569: 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 disease. 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 artery; MH, medial hallux; DH, distal hallux. Optoacoustic mesoscopy

570-492: A living mouse. Histology cross-sections of the tissue shown on the left. 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 analog-to-digital converters allow simultaneous data collection over 512 parallel elements, substantially shortening

665-460: 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. 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

760-427: A mixture, making absorption spectroscopy useful in wide variety of applications. For instance, Infrared gas analyzers can be used to identify the presence of pollutants in the air, distinguishing the pollutant from nitrogen, oxygen, water, and other expected constituents. The specificity also allows unknown samples to be identified by comparing a measured spectrum with a library of reference spectra. In many cases, it

855-415: 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 tumor, imaged using MSOT (left). MSOT detects photoechoes, i.e. ultrasound waves generated by thermo-elastic expansion of a sample (e.g. tissue) after absorption of transient electromagnetic energy. Typically,

950-489: 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 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. MSOT can detect exogenous contrast agents up to

1045-528: A sample and an instrument will contain the spectral information, so the measurement can be made remotely . Remote spectral sensing is valuable in many situations. For example, measurements can be made in toxic or hazardous environments without placing an operator or instrument at risk. Also, sample material does not have to be brought into contact with the instrument—preventing possible cross contamination. Remote spectral measurements present several challenges compared to laboratory measurements. The space in between

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1140-427: 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 Optoacoustic imaging in general and MSOT in particular may address

1235-564: 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. 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

1330-416: Is spectroscopy that involves techniques that measure the absorption of electromagnetic radiation , as a function of frequency or wavelength , due to its interaction with a sample. The sample absorbs energy, i.e., photons, from the radiating field. The intensity of the absorption varies as a function of frequency, and this variation is the absorption spectrum . Absorption spectroscopy is performed across

1425-404: Is synchrotron radiation , which covers all of these spectral regions. Other radiation sources generate a narrow spectrum, but the emission wavelength can be tuned to cover a spectral range. Examples of these include klystrons in the microwave region and lasers across the infrared, visible, and ultraviolet region (though not all lasers have tunable wavelengths). The detector employed to measure

1520-469: Is a particularly significant type of remote spectral sensing. In this case, the objects and samples of interest are so distant from earth that electromagnetic radiation is the only means available to measure them. Astronomical spectra contain both absorption and emission spectral information. Absorption spectroscopy has been particularly important for understanding interstellar clouds and determining that some of them contain molecules . Absorption spectroscopy

1615-400: Is a wide range of experimental approaches for measuring absorption spectra. The most common arrangement is to direct a generated beam of radiation at a sample and detect the intensity of the radiation that passes through it. The transmitted energy can be used to calculate the absorption. The source, sample arrangement and detection technique vary significantly depending on the frequency range and

1710-437: Is also common to employ interferometry to determine the spectrum— Fourier transform infrared spectroscopy is a widely used implementation of this technique. Two other issues that must be considered in setting up an absorption spectroscopy experiment include the optics used to direct the radiation and the means of holding or containing the sample material (called a cuvette or cell). For most UV, visible, and NIR measurements

1805-408: Is also employed in the study of extrasolar planets . Detection of extrasolar planets by transit photometry also measures their absorption spectrum and allows for the determination of the planet's atmospheric composition, temperature, pressure, and scale height , and hence allows also for the determination of the planet's mass. Theoretical models, principally quantum mechanical models, allow for

1900-470: 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). MSOT has now been used in a broad range of biological applications, including cardiovascular disease research, neuroimaging and cancer research . The development of real-time hand-held imaging systems has enabled clinical use of MSOT for imaging

1995-483: 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 metastatic status of sentinel lymph nodes in melanoma patients. It can also detect circulating melanoma cells. MSOT can detect several other endogenous tissue absorbers, as long as

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2090-451: Is in a liquid or solid phase and interacting more strongly with neighboring molecules. The width and shape of absorption lines are determined by the instrument used for the observation, the material absorbing the radiation and the physical environment of that material. It is common for lines to have the shape of a Gaussian or Lorentzian distribution. It is also common for a line to be described solely by its intensity and width instead of

2185-407: Is injected inside the primary tumor and 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

2280-399: 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 surrounding the target tissue. Typically, three-dimensional imaging systems achieve this by scanning a single ultrasound sensor around

2375-416: Is likely to be well suited to this application, since it can detect lipids, neovasculature, hemoglobin oxygenation and contrast agents that mark inflammation. 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

2470-403: Is more likely to be absorbed at frequencies that match the energy difference between two quantum mechanical states of the molecules . The absorption that occurs due to a transition between two states is referred to as an absorption line and a spectrum is typically composed of many lines. The frequencies at which absorption lines occur, as well as their relative intensities, primarily depend on

2565-482: Is possible to determine qualitative information about a sample even if it is not in a library. Infrared spectra, for instance, have characteristics absorption bands that indicate if carbon-hydrogen or carbon-oxygen bonds are present. An absorption spectrum can be quantitatively related to the amount of material present using the Beer–Lambert law . Determining the absolute concentration of a compound requires knowledge of

2660-558: 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 mesoscopy with exogenous agents may provide further useful information. 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

2755-478: Is that they must be approved individually for human use because their safety has not been well established. Gold nanoparticles , silver nanoparticles , carbon nanotubes , 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

2850-428: 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. 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,

2945-413: Is therefore broader yet. Absorption and transmission spectra represent equivalent information and one can be calculated from the other through a mathematical transformation. A transmission spectrum will have its maximum intensities at wavelengths where the absorption is weakest because more light is transmitted through the sample. An absorption spectrum will have its maximum intensities at wavelengths where

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3040-426: Is to generate radiation with a source, measure a reference spectrum of that radiation with a detector and then re-measure the sample spectrum after placing the material of interest in between the source and detector. The two measured spectra can then be combined to determine the material's absorption spectrum. The sample spectrum alone is not sufficient to determine the absorption spectrum because it will be affected by

3135-530: Is to optics: optical methods rely on photons, whereas optoacoustic methods rely on photoechoes or photoacoustic responses. Tomography . 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. Fig. 1: Operational capabilities of MSOT. Hybrid image showing an optical micrograph of part of

3230-442: Is typical. 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 diffraction. In other words, optoacoustic microscopy has the same limitations as conventional optical microscopy. Together, however,

3325-460: Is typically unfocused and selected 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 tumor . Regions of interest are approximately 50 mm, and resolution of 5-30 microns

3420-507: The Kramers–Kronig relations . Therefore, the absorption spectrum can be derived from a scattering or reflection spectrum. This typically requires simplifying assumptions or models, and so the derived absorption spectrum is an approximation. Absorption spectroscopy is useful in chemical analysis because of its specificity and its quantitative nature. The specificity of absorption spectra allows compounds to be distinguished from one another in

3515-477: The electromagnetic spectrum . Absorption spectroscopy is employed as an analytical chemistry tool to determine the presence of a particular substance in a sample and, in many cases, to quantify the amount of the substance present. Infrared and ultraviolet–visible spectroscopy are particularly common in analytical applications. Absorption spectroscopy is also employed in studies of molecular and atomic physics, astronomical spectroscopy and remote sensing. There

3610-419: The electronic and molecular structure of the sample. The frequencies will also depend on the interactions between molecules in the sample, the crystal structure in solids, and on several environmental factors (e.g., temperature , pressure , electric field , magnetic field ). The lines will also have a width and shape that are primarily determined by the spectral density or the density of states of

3705-482: The frequency range from around 20  kHz to around 300  GHz . This is roughly between the upper limit of audio frequencies and the lower limit of infrared frequencies, and also encompasses the microwave range. These are the frequencies at which energy from an oscillating current can radiate off a conductor into space as radio waves , so they are used in radio technology, among other uses. Different sources specify different upper and lower bounds for

3800-411: The absorber. A liquid or solid absorber, in which neighboring molecules strongly interact with one another, tends to have broader absorption lines than a gas. Increasing the temperature or pressure of the absorbing material will also tend to increase the line width. It is also common for several neighboring transitions to be close enough to one another that their lines overlap and the resulting overall line

3895-400: 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). MSOT has

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3990-402: The absorption is strongest. Emission is a process by which a substance releases energy in the form of electromagnetic radiation. Emission can occur at any frequency at which absorption can occur, and this allows the absorption lines to be determined from an emission spectrum. The emission spectrum will typically have a quite different intensity pattern from the absorption spectrum, though, so

4085-451: The absorption spectra of atoms and molecules to be related to other physical properties such as electronic structure , atomic or molecular mass , and molecular geometry . Therefore, measurements of the absorption spectrum are used to determine these other properties. Microwave spectroscopy , for example, allows for the determination of bond lengths and angles with high precision. In addition, spectral measurements can be used to determine

4180-505: 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, melanin , water, lipids and unknown metabolites , which further complicates unmixing. Recently, eigenspectra MSOT has been developed to model more accurately

4275-514: The accuracy of theoretical predictions. For example, the Lamb shift measured in the hydrogen atomic absorption spectrum was not expected to exist at the time it was measured. Its discovery spurred and guided the development of quantum electrodynamics , and measurements of the Lamb shift are now used to determine the fine-structure constant . The most straightforward approach to absorption spectroscopy

4370-565: 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. Fig. 3: Five-dimensional imaging of mouse brain perfusion in vivo. (a) Layout of

4465-487: The appropriate frequency can improve sensitivity at the target imaging depth, but at the cost of spatial resolution. 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 an in vivo detection sensitivity of 0.1-1 μM for organic dyes with

4560-1055: The body. That being said, there is limited studies on how effective these devices are. Test apparatus for radio frequencies can include standard instruments at the lower end of the range, but at higher frequencies, the test equipment becomes more specialized. While RF usually refers to electrical oscillations, mechanical RF systems are not uncommon: see mechanical filter and RF MEMS . ELF 3 Hz/100 Mm 30 Hz/10 Mm SLF 30 Hz/10 Mm 300 Hz/1 Mm ULF 300 Hz/1 Mm 3 kHz/100 km VLF 3 kHz/100 km 30 kHz/10 km LF 30 kHz/10 km 300 kHz/1 km MF 300 kHz/1 km 3 MHz/100 m HF 3 MHz/100 m 30 MHz/10 m VHF 30 MHz/10 m 300 MHz/1 m UHF 300 MHz/1 m 3 GHz/100 mm SHF 3 GHz/100 mm 30 GHz/10 mm EHF 30 GHz/10 mm 300 GHz/1 mm THF 300 GHz/1 mm 3 THz/0.1 mm Absorption spectra Absorption spectroscopy

4655-579: The breast, vasculature, lymph nodes and skin. Multi-spectral. MSOT collects images at multiple wavelengths and resolves the spectral signatures in each voxel 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- hemoglobin concentrations, and a third image resolving additional target photoabsorber(s). These additional photoabsorbers include melanin, fat, water and other endogenous or exogenous agents. Optoacoustic. This term denotes

4750-410: The clinic as MRI contrast agents. Targeted contrast agents 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 absorption spectrum changes as the result of

4845-504: The combination of optical (Greek, oπτικός) and acoustic (Greek, ακουστικός) energy (or components) in a single modality, which distinguishes optoacoustic imaging from optical imaging . Photoecho denotes the combination of light (Greek, Φως <phos>) and sound ( Ήχος <echos>) or reflection of sound Hχώ <echo>). The term photoacoustic is also widely used, and it denotes the generation of acoustic energy by light. Photoecho and photoacoustic are to optoacoustics what photon

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4940-429: The combined energy of the two changes. The energy associated with the quantum mechanical change primarily determines the frequency of the absorption line but the frequency can be shifted by several types of interactions. Electric and magnetic fields can cause a shift. Interactions with neighboring molecules can cause shifts. For instance, absorption lines of the gas phase molecule can shift significantly when that molecule

5035-442: The compound's absorption coefficient . The absorption coefficient for some compounds is available from reference sources, and it can also be determined by measuring the spectrum of a calibration standard with a known concentration of the target. One of the unique advantages of spectroscopy as an analytical technique is that measurements can be made without bringing the instrument and sample into contact. Radiation that travels between

5130-877: The contrast agent can be followed in real time. 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 the distributions of specific photoabsorbing molecules. The endogenous photoabsorbers most often imaged are oxy- and deoxy-hemoglobin, key players in oxygen metabolism , myoglobin , lipids , melanin 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 nanoparticles . Transfecting target tissue with reporter genes to express contrast agents in situ has also been reported, such as transfection with

5225-779: 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, with a strong peak at 980 nm. Bilirubin and cytochromes can be imaged at blue wavelengths. UV absorption by DNA has also been exploited to image cell nuclei. A multitude of exogenous contrast agents 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 agents exist. Organic dyes , such as

5320-522: The current proliferation of radio frequency wireless telecommunications devices such as cellphones . Medical applications of radio frequency (RF) energy, in the form of electromagnetic waves ( radio waves ) or electrical currents, have existed for over 125 years, and now include diathermy , hyperthermy treatment of cancer, electrosurgery scalpels used to cut and cauterize in operations, and radiofrequency ablation . Magnetic resonance imaging (MRI) uses radio frequency fields to generate images of

5415-449: The electromagnetic spectrum. For spectroscopy, it is generally desirable for a source to cover a broad swath of wavelengths in order to measure a broad region of the absorption spectrum. Some sources inherently emit a broad spectrum. Examples of these include globars or other black body sources in the infrared, mercury lamps in the visible and ultraviolet, and X-ray tubes . One recently developed, novel source of broad spectrum radiation

5510-409: The entire shape being characterized. The integrated intensity—obtained by integrating the area under the absorption line—is proportional to the amount of the absorbing substance present. The intensity is also related to the temperature of the substance and the quantum mechanical interaction between the radiation and the absorber. This interaction is quantified by the transition moment and depends on

5605-757: The esophagus and colon in rats and rabbits. The MSOT images revealed vascular features and 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. Miniaturized optoacoustic devices are also expected to offer interesting possibilities for intravascular imaging [72-74], improving our ability to detect atherosclerosis and stent-related biomarkers. Optoacoustic imaging

5700-443: The experimental conditions—the spectrum of the source, the absorption spectra of other materials between the source and detector, and the wavelength dependent characteristics of the detector. The reference spectrum will be affected in the same way, though, by these experimental conditions and therefore the combination yields the absorption spectrum of the material alone. A wide variety of radiation sources are employed in order to cover

5795-687: 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 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

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5890-419: The flexibility of MSOT, which reflects the range of contrast 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. Hemoglobin is the dominant absorber of light in the visible and near-IR part of

5985-878: 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 photodynamic therapy , can be detected using MSOT, allowing analysis of their pharmacokinetics and bio-distribution in vivo. Light-absorbing nanoparticles offer potential advantages over organic dyes because of their ability to produce stronger photoechoes and their lower photosensitivity. One disadvantage

6080-413: The frequencies that can be collected and processed for image reconstruction are determined by the ultrasound detector. Macroscopic MSOT 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

6175-722: The frequency range. Electric currents that oscillate at radio frequencies ( RF currents ) have special properties not shared by direct current or lower audio frequency alternating current , such as the 50 or 60 Hz current used in electrical power distribution . The radio spectrum of frequencies is divided into bands with conventional names designated by the International Telecommunication Union (ITU): Frequencies of 1 GHz and above are conventionally called microwave , while frequencies of 30 GHz and above are designated millimeter wave . More detailed band designations are given by

6270-413: The human body. Radio Frequency or RF energy is also being used in devices that are being advertised for weight loss and fat removal. The possible effects RF might have on the body and whether RF can lead to fat reduction needs further study. Currently, there are devices such as trusculpt ID , Venus Bliss and many others utilizing this type of energy alongside heat to target fat pockets in certain areas of

6365-416: 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 signals. 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

6460-443: The infrared, and photodiodes and photomultiplier tubes in the visible and ultraviolet. If both the source and the detector cover a broad spectral region, then it is also necessary to introduce a means of resolving the wavelength of the radiation in order to determine the spectrum. Often a spectrograph is used to spatially separate the wavelengths of radiation so that the power at each wavelength can be measured independently. It

6555-609: 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 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. The hemoglobin distribution in carotid arteries of healthy humans has recently been imaged in real time using

6650-460: The lymph nodes. 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 sentinel lymph node (in color), overlaid on a background image of tissue illuminated at

6745-411: The molecule and are typically found in the infrared region. Electronic lines correspond to a change in the electronic state of an atom or molecule and are typically found in the visible and ultraviolet region. X-ray absorptions are associated with the excitation of inner shell electrons in atoms. These changes can also be combined (e.g. rotation–vibration transitions ), leading to new absorption lines at

6840-683: 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 signal for MSOT. 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 advantages over other radiology modalities because of its ability to resolve oxygenated and deoxygenated hemoglobin, its compatibility with

6935-493: The near-IR range (e.g. red fluorescent protein ) 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, eGFP and mCherry fluorescent proteins have been imaged in model organisms such as Drosophila melanogaster pupae and adult zebrafish, and mCherry has been imaged in tumor cells in

7030-630: 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 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. Melanin

7125-412: The particular lower state the transition starts from, and the upper state it is connected to. The width of absorption lines may be determined by the spectrometer used to record it. A spectrometer has an inherent limit on how narrow a line it can resolve and so the observed width may be at this limit. If the width is larger than the resolution limit, then it is primarily determined by the environment of

7220-561: The photoabsorbers that can be seen and the imaging depth. High-energy ion beams and energy in the radiofrequency 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 macroscopic regime, involving resolution of 100-500 microns and penetration depth >10 mm, or mesoscopic range, involving resolution of 1-50 microns and penetration depth <10 mm.[6] Microscopic resolution

7315-492: 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 in laser source and detector technology, computed tomography and unmixing techniques. The capabilities and challenges of each MSOT dimension are described below. Optoacoustic (photoacoustic) imaging

7410-413: The purpose of the experiment. Following are the major types of absorption spectroscopy: Nuclear magnetic resonance spectroscopy A material's absorption spectrum is the fraction of incident radiation absorbed by the material over a range of frequencies of electromagnetic radiation. The absorption spectrum is primarily determined by the atomic and molecular composition of the material. Radiation

7505-466: The radiation power will also depend on the wavelength range of interest. Most detectors are sensitive to a fairly broad spectral range and the sensor selected will often depend more on the sensitivity and noise requirements of a given measurement. Examples of detectors common in spectroscopy include heterodyne receivers in the microwave, bolometers in the millimeter-wave and infrared, mercury cadmium telluride and other cooled semiconductor detectors in

7600-491: 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

7695-624: The sample are processed using tomographic reconstruction 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 wavelengths allow specific distinction of photoabsorbers with different optical absorption spectra , 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

7790-427: 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 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

7885-433: The sample of interest and the instrument may also have spectral absorptions. These absorptions can mask or confound the absorption spectrum of the sample. These background interferences may also vary over time. The source of radiation in remote measurements is often an environmental source, such as sunlight or the thermal radiation from a warm object, and this makes it necessary to distinguish spectral absorption from changes in

7980-573: 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. 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

8075-482: The sample, or by using one-dimensional or two-dimensional ultrasound sensor arrays to parallelize detection. 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 using focused ultrasound detectors to limit ultrasound detection to

8170-506: The source spectrum. To simplify these challenges, differential optical absorption spectroscopy has gained some popularity, as it focusses on differential absorption features and omits broad-band absorption such as aerosol extinction and extinction due to rayleigh scattering. This method is applied to ground-based, airborne, and satellite-based measurements. Some ground-based methods provide the possibility to retrieve tropospheric and stratospheric trace gas profiles. Astronomical spectroscopy

8265-415: The spectral responses of different photoabsorbers in three-dimensional tissue. This may help improve spectral unmixing and therefore image quality. MSOT can resolve various optoacoustic moieties based on their absorption spectrum, including nanoparticles, dyes and fluorochromes. Most fluorochromes are optimized for fluorescence emission and are sub-optimal for optoacoustic detection, because after absorbing

8360-470: The standard IEEE letter- band frequency designations and the EU/NATO frequency designations. Radio frequencies are used in communication devices such as transmitters , receivers , computers , televisions , and mobile phones , to name a few. Radio frequencies are also applied in carrier current systems including telephony and control circuits. The MOS integrated circuit is the technology behind

8455-408: The system. It is a branch of atomic spectra where, Absorption lines are typically classified by the nature of the quantum mechanical change induced in the molecule or atom. Rotational lines , for instance, occur when the rotational state of a molecule is changed. Rotational lines are typically found in the microwave spectral region. Vibrational lines correspond to changes in the vibrational state of

8550-467: The tissue, 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

8645-437: The two are not equivalent. The absorption spectrum can be calculated from the emission spectrum using Einstein coefficients . The scattering and reflection spectra of a material are influenced by both its refractive index and its absorption spectrum. In an optical context, the absorption spectrum is typically quantified by the extinction coefficient , and the extinction and index coefficients are quantitatively related through

8740-406: The two microscopies can provide more information than either on its own. MSOT can operate in three imaging modes: 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

8835-474: The tyrosinase gene to produce melanin. 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 can be merged to provide a complete picture of tissue oxygenation/hypoxia. By using hemoglobin as an intrinsic oxygen sensor, MSOT

8930-433: The ultrasound detector employed, the amount of light energy applied, the voxel 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

9025-431: The use of precision quartz cuvettes are necessary. In both cases, it is important to select materials that have relatively little absorption of their own in the wavelength range of interest. The absorption of other materials could interfere with or mask the absorption from the sample. For instance, in several wavelength ranges it is necessary to measure the sample under vacuum or in a noble gas environment because gases in

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