We present line scan reflectance diffuse optical tomography (LS-RDOT), a technique to generate quantitative cross-sectional images of hemoglobin concentration, tissue oxygen saturation, water content, and lipid content, for non-invasive bedside imaging of breast cancer. The LS-RDOT system is composed of a single-channel time-domain diffuse optical spectroscopy (TD-DOS) system measuring at wavelengths of 761, 802, 838, 908, 936, and 976 nm and hand-held probes with source–detector distances of 20, 30, and 40 mm. The line scans were performed by acquiring temporal point spread functions (TPSF) at 9 measurement points with a spacing of 5 mm linearly marked on the skin just above the breast lesion. The cross-sectional images were restored by an iterative image reconstruction method with an expression of the TPSF obtained from the photon diffusion equation using the Rytov approximation. A preliminary clinical measurement was conducted for a breast cancer patient with a tumor of approximately 10 mm in size. The reconstructed images captured changes in the physiological parameters of the breast cancer at the lesion location indicated by the ultrasonographic image. In addition, the results showed that LS-RDOT provides cross-sectional images of physiological parameters in a form that can be fused with structural images provided by ultrasonography
SignificanceThe water and lipid content of normal breast tissue showed mammary gland characteristics with less influence from the chest wall using six-wavelength time-domain diffuse optical spectroscopy (TD-DOS) in a reflectance geometry.AimTo determine the depth sensitivity of a six-wavelength TD-DOS system and evaluate whether the optical parameters in normal breast tissue can distinguish dense breasts from non-dense breasts.ApproachMeasurements were performed in normal breast tissue of 37 breast cancer patients. We employed a six-wavelength TD-DOS system to measure the water and lipid content in addition to the hemoglobin concentration. The breast density in mammography and optical parameters were then compared.ResultsThe depth sensitivity of the system for water and lipid content was estimated to be ∼15 mm. Our findings suggest that the influence of the chest wall on the water content is weaker than that on the total hemoglobin concentration. In data with evaluation conditions, the water content was significantly higher (p < 0.001) and the lipid content was significantly lower (p < 0.001) in dense breast tissue. The water and lipid content exhibited a high sensitivity and specificity to distinguish dense from non-dense breasts in receiver-operating-characteristic curve analysis.ConclusionsWith less influence from the chest wall, the water and lipid content of normal breast tissue measured by a reflectance six-wavelength TD-DOS system, together with ultrasonography, can be applied to distinguish dense from non-dense breasts.
We report a time-domain reflectance diffuse optical tomography (TD-RDOT) system for providing three-dimensional images of hemoglobin concentration, tissue oxygen saturation, water and lipid contents of breast cancer from reflectance measurements. A scan area of 5 × 5 grid points with a 10-mm spacing is marked on the breast surface so that the tumor is just below the center of the area. The breast scan is performed by measuring the temporal profiles of six wavelengths at each grid point using a time-domain diffuse optical spectroscopy (TD-DOS) system and a hand-held probe. The TDDOS system that we developed is capable of measuring water and lipid contents and hemoglobin concentration. The hand-held probe is designed to measure the breast in reflectance mode with a source-to-detector separation of 20 mm. The three-dimensional distributions of the tissue parameters are restored using an iterative image reconstruction method. As a preliminary clinical demonstration, a breast cancer patient with a tumor size of approximately 20 mm was examined with the TD-RDOT. The reconstructed images show that the breast cancer had high hemoglobin concentration and water content, and low tissue oxygen saturation and lipid content. The results indicate that the TD-RDOT system has the potential to provide diagnostically relevant information on the tissue characteristics of the tumor at the bedside.
Time-domain (TD) near-infrared spectroscopy (NIRS) is an effective method of quantifying optical and biological properties, such as the mean optical path length, absorption coefficient, reduced scattering coefficient, and oxyhemoglobin and deoxy-hemoglobin concentrations of biological tissues. In addition to these parameters, water and lipid contents are important biological parameters expected to be useful information in clinical application. For our previous TD-NIRS systems, we used three wavelengths (760, 800, and 830 nm) that are sensitive to oxy- and deoxy-hemoglobin. To quantitatively measure water and lipid contents of biological tissues, we developed a new TD-NIRS system with three additional wavelengths (908, 936, and 976 nm) that are sensitive to water and lipids. The new six-wavelength TDNIRS system comprises six-wavelength pulsed light sources, two types of photomultiplier tubes (GaAs and InGaAs PMTs), a time-correlated single-photon counting unit, and optical fiber bundles. In this pilot study, we present the measurement results of oxy- and deoxy-hemoglobin concentrations, tissue oxygen saturation, and water and lipid contents at the calf, forearm, and abdomen of five healthy adult volunteers in a resting state using the six-wavelength TD-NIRS system. We thus confirmed that the fat thickness measured by ultrasonography and the water content measured by the six-wavelength TD-NIRS system were negatively correlated, whereas the fat thickness and lipid content were positively correlated. We expect that the six-wavelength TD-NIRS system will be used in clinical studies as a point-of-care testing device for the bedside monitoring of human subjects.
The purpose of this study was to evaluate the effects of the thickness and depth of tumors on hemoglobin measurements in breast cancer by optical spectroscopy and to demonstrate tissue oxygen saturation (SO2) and reduced scattering coefficient (μs′) in breast tissue and breast cancer in relation to the skin-to-chest wall distance. We examined 53 tumors from 44 patients. Total hemoglobin concentration (tHb), SO2, and μs′ were measured by time-resolved spectroscopy (TRS). The skin-to-chest wall distance and the size and depth of tumors were measured by ultrasonography. There was a positive correlation between tHb and tumor thickness, and a negative correlation between tHb and tumor depth. SO2 in breast tissue decreased when the skin-to-chest wall distance decreased, and SO2 in tumors tended to be lower than in breast tissue. In breast tissue, there was a negative correlation between μs′ and the skin-to-chest wall distance, and μs′ in tumors was higher than in breast tissue. Measurement of tHb in breast cancer by TRS was influenced by tumor thickness and depth. Although SO2 seemed lower and μs′ was higher in breast cancer than in breast tissue, the skin-to-chest wall distance may have affected the measurements.
We developed a transportable Linnik-type full-field low-coherent quantitative phase microscope that is able to compensate for optical path length (OPL) disturbance due to environmental mechanical noises. Though two-beam interferometers such as Linnik ones suffer from unstable OPL difference, we overcame this problem with a mechanical feedback system based on digital signal-processing that controls the OPL difference in sub-nanometer resolution precisely with a feedback bandwidth of 4 kHz. The developed setup has a footprint of 200 mm by 200 mm, a height of 500 mm, and a weight of 4.5 kilograms. In the transmission imaging mode, cells were cultured on a reflection-enhanced glass-bottom dish, and we obtained interference images sequentially while performing stepwise quarter-wavelength phase-shifting. Real-time image processing, including retrieval of the unwrapped phase from interference images and its background correction, along with the acquisition of interference images, was performed on a laptop computer. Emulation of the phase contrast (PhC) images and the differential interference contrast (DIC) images was also performed in real time. Moreover, our setup was applied for full-field cell membrane imaging in the reflection mode, where the cells were cultured on an anti-reflection (AR)-coated glass-bottom dish. The phase and intensity of the light reflected by the membrane revealed the outer shape of the cells independent of the refractive index. In this paper, we show imaging results on cultured cells in both transmission and reflection modes.
We developed a compact Mach-Zehnder interferometer module to be used as a replacement of the objective lens in a conventional inverted microscope (Nikon, TS100-F) in order to make them quantitative phase microscopes. The module has a 90-degree-flipped U-shape; the dimensions of the module are 160 mm by 120 mm by 40 mm and the weight is 380 grams. The Mach-Zehnder interferometer equipped with the separate reference and sample arms was implemented in this U-shaped housing and the path-length difference between the two arms was manually adjustable. The sample under test was put on the stage of the microscope and a sample light went through it. Both arms had identical achromatic lenses for image formation and the lateral positions of them were also manually adjustable. Therefore, temporally and spatially low coherent illumination was applicable because the users were able to balance precisely the path length of the two arms and to overlap the two wavefronts. In the experiment, spectrally filtered LED light for illumination (wavelength = 633 nm and bandwidth = 3 nm) was input to the interferometer module via a 50 micrometer core optical fiber. We have successfully captured full-field interference images by a camera put on the trinocular tube of the microscope and constructed quantitative phase images of the cultured cells by means of the quarter-wavelength phase shifting algorithm. The resultant quantitative phase images were speckle-free and halo-free due to spectrally and spatially low coherent illumination.
We developed a time-resolved reflectance diffuse optical tomography (RDOT) system to measure tumor responses to chemotherapy in breast cancer patients at the bedside. This system irradiates the breast with a three-wavelength pulsed laser (760, 800, and 830 nm) through a source fiber specified by an optical switch. The light collected by detector fibers is guided to a detector unit consisting of variable attenuators and photomultiplier tubes. Thirteen irradiation and 12 detection points were set to a measurement area of 50 × 50 mm for a hand-held probe. The data acquisition time required to obtain the temporal profiles within the measurement area is about 2 minutes. The RDOT system generates topographic and tomographic images of tissue properties such as hemoglobin concentration and tissue oxygen saturation using two imaging methods. Topographic images are obtained from the optical properties determined for each source-detector pair using a curve-fitting method based on the photon diffusion theory, while tomographic images are reconstructed using an iterative image reconstruction method. In an experiment using a tissue-like solid phantom, a tumor-like cylindrical target (15 mm diameter, 15 mm high) embedded in a breast tissue-like background medium was successfully reconstructed. Preliminary clinical measurements indicated that the tumor in a breast cancer patient was detected as a region of high hemoglobin concentration. In addition, the total hemoglobin concentration decreased during chemotherapy. These results demonstrate the potential of RDOT for evaluating the effectiveness of chemotherapy in patients with breast cancer.
KEYWORDS: Absorption, Mammography, Breast, Breast cancer, Scattering, 3D image reconstruction, Magnetic resonance imaging, Imaging systems, 3D modeling, Time resolved spectroscopy
A diffused optical mammography composed of a 48-channel time-resolved spectroscopy system is being developed for
breast cancer diagnosis. The system utilizes the time-correlated single photon counting method, and the detector
modules and the signal processing circuits were custom made to obtain a high signal to noise ratio and high temperature
stability with a high temporal resolution. Pulsed light generated by a Ti:Sapphire laser was irradiated to the breast, and
the transmitted light was collected by optical fibers placed on the surface of a hemispherical gantry filled with an optical
matching fluid. To reconstruct a 3D image of the breast, we employed a method using time-resolved photon path
distribution (time-resolved PPD) based on the assumption that scattering and absorption are independent of each other.
As it is not necessary to recalculate the time-resolved PPD corresponding to any changes in the absorption, we can obtain
the reconstructed image quickly. The clinical research was started in January 2007. In a comparative study with
conventional modalities, the breast cancers were detected as optically higher absorption regions. Moreover, it was
suggested that the optical mammography is useful in monitoring the effect of chemotherapy.
We propose a new algorithm for optical computed tomography (CT) to quantify the absorptive substances in highly scattering media such as human tissues. Our algorithm uses the uniform medium in which scattering and absorption coefficients are equivalent to the average coefficients of the actual object to be measured. In other words, we use an imaginary reference. When the weight function and re-emissions are measurable or can be calculated for the imaginary reference, we can describe the inside structure of the non-uniform object using the deviation of the absorption coefficient from the average value. Since it is difficult to prepare a phantom of which exterior shape and inside structure are identical to that of the real objects, conventional methods cannot be free from the significant errors. The averages of the absorption and scattering coefficients are obtained by measurements such as time-resolved spectroscopy. The weight function and re- missions can be calculated using the average values by a Monte Carlo simulation or a finite difference method. The absolute absorption coefficient is obtained as the sum of the average and the deviation. The validity of our algorithm was confirmed by measuring a tissue-like phantom which contains three different absorbers. We evaluated reconstructed images and confirmed that the new method gives better accuracy in the quantitation of the concentration of absorbing substance and a smaller image distortion. Our results have significant implications for optical CT which quantifies the concentration of absorbing substances accurately without measuring the reference phantom.
Near IR time resolved spectroscopy has been studied for quantitative determination of absorbance in highly scattering medium such as tissue. When a very narrow optical pulse is incedent into a scattering medium, the detected pulse through the medium broadens and the temporal profile is closely related to the optical property of the scattering medium. The photon migration in highly scattering medium can be described with the diffusion theory. Thus the optical property of the scattering medium can be determined by analyzing the shape of the detected tamporal profile with the diffusion equation. We have developed the time resolved spectroscopy (TRS) system based on a time correlated single photon counting technique for data acquisition and diffusion theory for data analysis. Pulsed laser diodes with two different wavelengths are used as light sources in the system. The system size is compact and it can be moved around a laboratory or hospital easily. We demonstrated its use in vivo experiments. As a result, we were able to accurately determine absorber concentrations in a highly scattering medium and the result of these in vivo experiments indicate possible use of the system for quantitative clinical studies.
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