Frequency-domain Photon Migration Research Articles

Narrowband diffuse reflectance spectroscopy in the 900-1000 nm wavelength region to quantify water and lipid content of turbid media.

We report a narrow wavelength band diffuse reflectance spectroscopy (nb-DRS) method to determine water and fat ratios of scattering media in the 900-1000 nm range. This method was shown to be linearly correlated with absolute water and fat concentrations as tested on a set of turbid emulsion phantoms with a range of water and lipid compositions. Robustness to scattering assumptions was demonstrated and compared against measured scattering by a frequency-domain photon migration system. nb-DRS was also tested on ex-vivo porcine samples and compared against direct tissue water extraction by analytical chemistry methods. We speculate nb-DRS has potential applications in portable devices such as clinical and digital health wearables.

Photon phase shift imaging research on frequency domain diffuse optic tomography

Diffuse optic imaging is an important biomedical optic research tool. Diffuse optic tomography (DOT) modality needs progressive philosophical approaches for scientific contribution. Technological developments and philosophical approaches should both go forward. Phase-shift based frequency domain diffuse optical tomography (FDDOT) method was well established in the literature. The instruments were tested for brain neurofunctional imaging. A mixture of AC laser intensity and phase data were used at these works. According to those works, deep tissue resolution was improved by only using phase data. Because phase data is only related to the photon mean free path in imaging tissue media. Besides this advantage, laser intensity data is also affected by noisy background light and electrical artifacts. Another most important advantage of only using phase data can be explained as time-resolved temporal change which can be directly related to the phase shift of modulated frequency source. In this work, the FDDOT imaging method which uses phase shift data were tested for simulation. Laser source-driven forward model problem weight matrix simulation data was given to the simple pseudo-inverse-based inverse problem solution algorithm for one inclusion example. The inclusion image was reconstructed and demonstrated successfully. Forward model problem weight functions inside the tissue simulation media were calculated and used based on the phase shifts at the same core modulation frequency. 100 MHz modulation frequency was selected due to its FDDOT standard. 13 sources and 13 detectors were placed on the back-reflected imaging surface. 40 x, y, z cartesian coordinate grid elements were used in the image reconstruction algorithm. Photon absorption coefficient: μa = 0.1 cm−1, and scattering coefficient: μs = 100 cm−1 values were set for simulation background. One inclusion object was embedded inside the background imaging tissue simulation environment. x, y, z cartesian coordinate grid sizes were selected for 1 μm for each direction. Photon phase shift fluencies were added to the forward model problem. The forward model problem was built according to the frequency domain photon migration diffusion equation (DE) approximation. The pseudoinverse mathematical inverse problem solution function was applied to test the results. The embedded inclusion object was reconstructed successfully with the high-resolution image quality. The philosophical approach has future promising DOT imaging capability. The phase shift version of the FDDOT modality has an important advantage for future purposes.

Monocular 3D Probe Tracking for Generating Sub-Surface Optical Property Maps From Diffuse Optical Spectroscopic Imaging.

Diffuse optical spectroscopic imaging (DOSI) is a promising biophotonic technology for clinical tissue assessment, but is currently hampered by difficult wide area assessment. A co-integrative optical imaging system is proposed for dense sub-surface optical property spatial assessment. The proposed system fuses a co-aligned set of camera frames and diffuse optical spectroscopy measurements to generate spatial sub-surface optical property maps. A 3D rigid body motion estimation model was developed by fitting automatically detected target features to an a priori geometric model using a single overhead camera. Point-wise optical properties were measured across the tissue using frequency domain photon migration DOSI. The 3D probe trajectory and temporal optical property data were fused to generate 2D spatial optical property maps, which were projected onto the tissue image using pre-calibrated camera parameters. The system demonstrated sub-millimeter positional accuracy (error 0.24 ± 0.35mm) across different probe speeds (1.0-3.8cm/s), and displacement accuracy in overhead ([Formula: see text]mm) and tilted (0.51 ± 0.51mm) camera orientations. Unstructured scans on a tumor inclusion phantom showed strong contrast under different probe paths, and significant ( ) changes in optical properties in an in vivo leg cuff occlusion protocol with spatial anatomy localization. The proposed co-integrative optical imaging system generated dense sub-surface optical property distributions across wide tissue areas with sub-millimeter accuracy at different probe speeds and trajectories, and does not require pre-planned probe route for tissue assessment. This system provides a valuable tool for real-time non-invasive tissue health and cancer screening, and enables longitudinal disease progression assessment through unstructured probe-based optical tissue assessment.

Vertical-cavity surface-emitting laser sources for gigahertz-bandwidth, multiwavelength frequency-domain photon migration.

.Frequency-domain photon migration (FDPM) uses modulated laser light to measure the bulk optical properties of turbid media and is increasingly applied for noninvasive functional medical imaging in the near-infrared. Although semiconductor edge-emitting laser diodes have been traditionally used as miniature light sources for this application, we show that vertical-cavity surface-emitting lasers (VCSELs) exhibit output power and modulation performance characteristics suitable for FDPM measurements of tissue optical properties at modulation frequencies exceeding 1 GHz. We also show that an array of multiple VCSEL devices can be coherently modulated at frequencies suitable for FDPM and can improve optical power. In addition, their small size and simple packaging make them an attractive choice as components in wearable sensors and clinical FDPM-based optical spectroscopy systems. We demonstrate the benefits of VCSEL technology by fabricating and testing a unique, compact VCSEL-based optical probe with an integrated avalanche photodiode. We demonstrate sensitivity of the VCSEL-based probe to subcutaneous tissue hemodynamics that was induced during an arterial cuff occlusion of the upper arm in a human subject.

Performance assessment of diffuse optical spectroscopic imaging instruments in a 2-year multicenter breast cancer trial

We present a framework for characterizing the performance of an experimental imaging technology, diffuse optical spectroscopic imaging (DOSI), in a 2-year multicenter American College of Radiology Imaging Network (ACRIN) breast cancer study (ACRIN-6691). DOSI instruments combine broadband frequency-domain photon migration with time-independent near-infrared (650 to 1000 nm) spectroscopy to measure tissue absorption and reduced scattering spectra and tissue hemoglobin, water, and lipid composition. The goal of ACRIN-6691 was to test the effectiveness of optically derived imaging endpoints in predicting the final pathologic response of neoadjuvant chemotherapy (NAC). Sixty patients were enrolled over a 2-year period at participating sites and received multiple DOSI scans prior to and during 3- to 6-month NAC. The impact of three sources of error on accuracy and precision, including different operators, instruments, and calibration standards, was evaluated using a broadband reflectance standard and two different solid tissue-simulating optical phantoms. Instruments showed <0.0010 mm−1 (10.3%) and 0.06 mm−1 (4.7%) deviation in broadband absorption and reduced scattering, respectively, over the 2-year duration of ACRIN-6691. These variations establish a useful performance criterion for assessing instrument stability. The proposed procedures and tests are not limited to DOSI; rather, they are intended to provide methods to characterize performance of any instrument used in translational optical imaging.

Pathlength determination for gas in scattering media absorption spectroscopy.

Gas in scattering media absorption spectroscopy (GASMAS) has been extensively studied and applied during recent years in, e.g., food packaging, human sinus monitoring, gas diffusion studies, and pharmaceutical tablet characterization. The focus has been on the evaluation of the gas absorption pathlength in porous media, which a priori is unknown due to heavy light scattering. In this paper, three different approaches are summarized. One possibility is to simultaneously monitor another gas with known concentration (e.g., water vapor), the pathlength of which can then be obtained and used for the target gas (e.g., oxygen) to retrieve its concentration. The second approach is to measure the mean optical pathlength or physical pathlength with other methods, including time-of-flight spectroscopy, frequency-modulated light scattering interferometry and the frequency domain photon migration method. By utilizing these methods, an average concentration can be obtained and the porosities of the material are studied. The last method retrieves the gas concentration without knowing its pathlength by analyzing the gas absorption line shape, which depends upon the concentration of buffer gases due to intermolecular collisions. The pathlength enhancement effect due to multiple scattering enables also the use of porous media as multipass gas cells for trace gas monitoring. All these efforts open up a multitude of different applications for the GASMAS technique.

Higher-order modulations of fs laser pulses for GHz frequency domain photon migration system

Except the fundamental modulation frequency, by higher-order-harmonic modulations of mode-locked laser pulses and a simple frequency demodulation circuit, a novel approach to GHz frequency-domain-photon-migration (FDPM) system was reported. With this novel approach, a wide-band modulation frequency comb is available without any external modulation devices and the only electronics to extract the optical attenuation and phase properties at a selected modulation frequency in FDPM systems are good mixers and lock-in devices. This approach greatly expands the frequency range that could be achieved by conventional FDPM systems and suggests that our system could extract much more information from biological tissues than the conventional FDPM systems. Moreover, this demonstration will be beneficial for discerning the minute change of tissue properties.

Light propagation in porous ceramics: porosity and optical property studies using tunable diode laser spectroscopy

By integrating gas in scattering media absorption spectroscopy and frequency domain photon migration a new method is developed for the study of optical porosity and optical properties of porous media, in our case ceramics. The optical porosity is defined as the ratio of the path length through the gas-filled pores and the physical path length through the whole medium. The effective refractive index of the porous ceramics is also retrieved based on the optical porosity, which is then used to evaluate the reduced scattering coefficients of the porous ceramics. The combined method provides a new way to study light propagation in porous media. A modified Looyenga model is proposed to study the relationship between the physical porosity and the effective refractive index of the porous medium, which also connects the optical and physical porosities, and provides the possibility to use the present method for porosimetry analysis.

Measuring tumor cycling hypoxia and angiogenesis using a side‐firing fiber optic probe

Hypoxia and angiogenesis can significantly influence the efficacy of cancer therapy and the behavior of surviving tumor cells. There is a growing demand for technologies to measure tumor hypoxia and angiogenesis temporally in vivo to enable advances in drug development and optimization. This paper reports the use of frequency-domain photon migration with a side-firing probe to quantify tumor oxygenation and hemoglobin concentrations in nude rats bearing human head/neck tumors administered with carbogen gas, cycling hypoxic gas or just room air. Significant increase (with carbogen gas breathing) or decrease (with hypoxic gas breathing) in tumor oxygenation was observed. The trend in tumor oxygenation during forced cycling hypoxia (CH) followed that of the blood oxygenation measured with a pulse oximeter. Natural CH was also observed in rats under room air. The studies demonstrated the potential of the technology for longitudinal monitoring of tumor CH during tumor growth or in response to therapy.

A compact frequency-domain photon migration system for integration into commercial hybrid small animal imaging scanners for fluorescence tomography

The work presented herein describes the system design and performance evaluation of a miniaturized near-infrared fluorescence (NIRF) frequency-domain photon migration (FDPM) system with non-contact excitation and homodyne detection capability for small animal fluorescence tomography. The FDPM system was developed specifically for incorporation into a Siemens micro positron emission tomography/computed tomography (microPET/CT) commercial scanner for hybrid small animal imaging, but could be adapted to other systems. Operating at 100 MHz, the system noise was minimized and the associated amplitude and phase errors were characterized to be ±0.7% and ±0.3°, respectively. To demonstrate the tomographic ability, a commercial mouse-shaped phantom with 50 µM IRDye800CW and 68Ga containing inclusion was used to associate PET and NIRF tomography. Three-dimensional mesh generation and anatomical referencing was accomplished through CT. A third-order simplified spherical harmonics approximation (SP3) algorithm, for efficient prediction of light propagation in small animals, was tailored to incorporate the FDPM approach. Finally, the PET-NIRF target co-localization accuracy was analyzed in vivo with a dual-labeled imaging agent targeting orthotopic growth of human prostate cancer. The obtained results validate the integration of time-dependent fluorescence tomography system within a commercial microPET/CT scanner for multimodality small animal imaging.

Digital parallel frequency-domain spectroscopy for tissue imaging

Near-infrared (NIR) (650 to 1000 nm) optical properties of turbid media can be quantified accurately and noninvasively using methods based on diffuse reflectance or transmittance, such as frequency-domain photon migration (FDPM). Conventional FDPM techniques based on white-light steady-state (SS) spectral measurements in conjunction with the acquisition of frequency-domain (FD) data at selected wavelengths using laser diodes are used to measure broadband NIR scattering-corrected absorption spectra of turbid media. These techniques are limited by the number of wavelength points used to obtain FD data and by the sweeping technique used to collect FD data over a relatively large range. We have developed a method that introduces several improvements in the acquisition of optical parameters, based on the digital parallel acquisition of a comb of frequencies and on the use of a white laser as a single light source for both FD and SS measurements. The source, due to the high brightness, allows a higher penetration depth with an extremely low power on the sample. The parallel acquisition decreases the time required by standard serial systems that scan through a range of modulation frequencies. Furthermore, all-digital acquisition removes analog noise, avoids the analog mixer, and does not create radiofrequency interference or emission.

Frequency domain photon migration measurements of dense monodisperse charged lattices and analysis using solutions of Ornstein Zernike equations

Isotropic scattering coefficient measurements were made of monodisperse polystyrene lattices of two different diameters of 144nm and 223nm and at volume fractions ranging from 0.15 to 0.22, using frequency domain photon migration measurements at wavelengths of 660, 685, 785 and 828nm. The isotropic scattering coefficient measurements were shown to be sensitive to the changing ionic strength (0.5–4mM, NaCl equiv.) of the dispersions exhibiting hindered scattering owing to structure at the lowest ionic strength values. Monte Carlo simulations and numerical solution of the Ornstein Zernike equations were used to compute isotropic scattering coefficients for comparison to measured values. The interaction potential was modeled as a hard sphere Yukawa potential and the Hypernetted Chain closure was used to solve the OZ equation. Effective particle charges were found after renormalization of the bare particle charge and used to predict the isotropic scattering coefficient. The model data were found to follow similar trends as experimental measurements. The refractive index of the particles has found to be an important factor for predicting experimental isotropic scattering coefficient values.

Combined optical porosimetry and gas absorption spectroscopy in gas-filled porous media using diode-laser-based frequency domain photon migration

A combination method of frequency domain photon migration (FDPM) and gas in scattering media absorption spectroscopy (GASMAS) is used for assessment of the mean optical path length (MOPL) and the gas absorption in gas-filled porous media, respectively. Polystyrene (PS) foams, with extremely high physical porosity, are utilized as sample materials for proof-of-principle demonstration. The optical porosity, defined as the ratio between the path length through the pores and the path length through the medium, is evaluated in PS foam and found consistent with the measured physical porosity. The method was also utilized for the study of balsa and spruce wood samples.

Digital Parallel Acquisition in Frequency Domain for the Characterization of Tissue Spatial Heterogeneities

Near-infrared (NIR) (650-1000 nm) optical properties of turbid media can be accurately quantified noninvasively using methods based on diffuse reflectance or transmittance, such as frequency domain photon migration (FDPM). For instance, Diffuse Optical Spectroscopy (DOS) is a noninvasive technique that is commonly used to provide biochemical information on hemoglobin, bulk lipids and water concentration by NIR tissue absorption and scattering. DOS does not require exogenous contrast, and rapidly provides quantitative, functional information about tumor biochemical composition. Conventional FDPM techniques are based on white-light steady-state (SS) measurements and the acquisition of frequency-domain (FD) data at several wavelengths using laser diodes, to measure broadband NIR scatter-corrected absorption spectra of turbid media. These techniques are limited by the number of wavelength points used to obtain the FD data. We developed a new method to improve the acquisition of optical parameters of the examined tissues, based on digital parallel acquisition in FD. With our system, both FD and SS measurements are performed using a super-continuum white laser alone. Moreover, the white laser allows a continuous scan of frequencies in the spectral medical window, thus providing additional wavelength information. At each wavelength, we extract what we refer to be as the tissue phasor. The estimated absorption and scattering coefficients are obtained by fitting phase shift and demodulation with a mathematical model for a semi-infinite geometry. In previous works we showed the possibility of noninvasively predicting chemotherapy response prior to treatment based on biomarkers obtained from tumor spatial heterogeneities of spectral features measured using a conventional DOS instrument. With the method here presented, we expect to improve the characterization of breast tumor spatial heterogeneities and the prediction of chemotherapy outcome. Work supported by NIH-P41-RR003155.

Motion-gated acquisition for in vivo optical imaging

Wide-field continuous wave fluorescence imaging, fluorescence lifetime imaging, frequency domain photon migration, and spatially modulated imaging have the potential to provide quantitative measurements in vivo. However, most of these techniques have not yet been successfully translated to the clinic due to challenging environmental constraints. In many circumstances, cardiac and respiratory motion greatly impair image quality and/or quantitative processing. To address this fundamental problem, we have developed a low-cost, field-programmable gate array-based, hardware-only gating device that delivers a phase-locked acquisition window of arbitrary delay and width that is derived from an unlimited number of pseudo-periodic and nonperiodic input signals. All device features can be controlled manually or via USB serial commands. The working range of the device spans the extremes of mouse electrocardiogram (1000 beats per minute) to human respiration (4 breaths per minute), with timing resolution <or=0.06%, and jitter <or=0.008%, of the input signal period. We demonstrate the performance of the gating device, including dramatic improvements in quantitative measurements, in vitro using a motion simulator and in vivo using near-infrared fluorescence angiography of beating pig heart. This gating device should help to enable the clinical translation of promising new optical imaging technologies.

Diffuse optical spectroscopy measurements of healing in breast tissue after core biopsy: case study

Diffuse optical spectroscopy (DOS) has been used to monitor and predict the effects of neoadjuvant (i.e., presurgical) chemotherapy in breast cancer patients in several pilot studies. Because patients with suspected breast cancers undergo biopsy prior to treatment, it is important to understand how biopsy trauma influences DOS measurements in the breast. The goal of this study was to measure the effects of a standard core breast biopsy on DOS measurements of tissue deoxyhemoglobin, hemoglobin, water, and bulk lipid concentrations. We serially monitored postbiopsy effects in the breast tissue in a single subject (31-year-old premenopausal female) with a 37x18x20 mm fibroadenoma. A baseline measurement and eight weekly postbiopsy measurements were taken with a handheld DOS imaging instrument. Our instrument used frequency domain photon migration combined with broadband steady-state spectroscopy to characterize tissues via quantitative measurements of tissue absorption and reduced scattering coefficients from 650 to 1000 nm. The concentrations of significant near-infrared (NIR) absorbers were mapped within a 50 cm(2) area over the biopsied region. A 2-D image of a contrast function called the tissue optical index (TOI=deoxyhemoglobinxwaterbulk lipid) was generated and revealed that a minimum of 14 days postbiopsy was required to return TOI levels in the biopsied area to their prebiopsy levels. Changes in the TOI images of the fibroadenoma also reflected the progression of the patient's menstrual cycle. DOS could therefore be useful in evaluating both wound-healing response and the effects of hormone and hormonal therapies in vivo.

Assessing the future of diffuse optical imaging technologies for breast cancer management

Diffuse optical imaging (DOI) is a noninvasive optical technique that employs near-infrared (NIR) light to quantitatively characterize the optical properties of thick tissues. Although NIR methods were first applied to breast transillumination (also called diaphanography) nearly 80 years ago, quantitative DOI methods employing time- or frequency-domain photon migration technologies have only recently been used for breast imaging (i.e., since the mid-1990s). In this review, the state of the art in DOI for breast cancer is outlined and a multi-institutional Network for Translational Research in Optical Imaging (NTROI) is described, which has been formed by the National Cancer Institute to advance diffuse optical spectroscopy and imaging (DOSI) for the purpose of improving breast cancer detection and clinical management. DOSI employs broadband technology both in near-infrared spectral and temporal signal domains in order to separate absorption from scattering and quantify uptake of multiple molecular probes based on absorption or fluorescence contrast. Additional dimensionality in the data is provided by integrating and co-registering the functional information of DOSI with x-ray mammography and magnetic resonance imaging (MRI), which provide structural information or vascular flow information, respectively. Factors affecting DOSI performance, such as intrinsic and extrinsic contrast mechanisms, quantitation of biochemical components, image formation/visualization, and multimodality co-registration are under investigation in the ongoing research NTROI sites. One of the goals is to develop standardized DOSI platforms that can be used as stand-alone devices or in conjunction with MRI, mammography, or ultrasound. This broad-based, multidisciplinary effort is expected to provide new insight regarding the origins of breast disease and practical approaches for addressing several key challenges in breast cancer, including: Detecting disease in mammographically dense tissue, distinguishing between malignant and benign lesions, and understanding the impact of neoadjuvant chemotherapies.

Improved accuracy of frequency-domain photon migration close to light source using delta–P1 approximation of the adjustable parameter f

The δ–P1 approximation can improve the accuracy of the diffusion equation in the near field. Usually, the method to determine the fractional forward-scattering peak f in the δ–P1 approximation is to compare the first two moments of the Henyey–Greenstein phase function and those of the δ–Eddington phase function. The error relative to Monte Carlo estimation still exists within a mean free path using the value f above. To overcome this defect, we put forward a new method to determine the parameter f for improving the accuracy of frequency-domain photon migration in the δ–P1 approximation if the detector is close to a light source. Results demonstrate that the adjustable f δ–P1 approximation can accurately predict photon fluence rate at distances less than half the transport mean free paths from the source.

Design and testing of a miniature broadband frequency domain photon migration instrument

A board-level broadband frequency domain photon migration (mini-FDPM) instrument has been constructed to replace a conventional network-analyzer-based FDPM instrument. The mini-FDPM instrument with four wavelengths (681, 783, 823, and 850 nm), matches conventional FDPM instrument in performance (-88 dBm noise level, 100 dB dynamic range) and bandwidth (1 GHz), and recovers the same optical properties within about 6% in absorption and 4% in reduced scattering for liquid phantoms covering a wide range of relevant optical properties. Compared to the conventional FDPM instrument, the mini-FDPM instrument is more than 5x faster (approximately 200 ms per 401 modulation frequencies) and several orders of magnitude less in size and cost. Standard fiber-optic-based probes can be used with the mini-FDPM instrument, which increases applications in a number of clinically relevant measurement scenarios. By drastically reducing size and cost, FDPM miniaturization lowers barriers to access and will help promote FDPM in clinical research problems. The mini-FDPM instrument forms the core of a modular broadband diffuse optical spectroscopy instrument that can be used for a variety of clinical problems in imaging and functional monitoring (i.e., breast/skin cancer, brain activation, and exercise physiology).

In vivo determination of skin near-infrared optical properties using diffuse optical spectroscopy

We develop a superficial diffusing probe with a 3 mm source-detector separation that can be used in combination with diffuse optical spectroscopic (DOS) methods to noninvasively determine full-spectrum optical properties of superficial in vivo skin in the wavelength range from 650 to 1000 nm. This new probe uses a highly scattering layer to diffuse photons emitted from a collimated light source and relies on a two-layer diffusion model to determine tissue absorption coefficient mu a and reduced scattering coefficient mu's. By employing the probe to measure two-layer phantoms that mimic the optical properties of skin, we demonstrate that the probe has an interrogation depth of 1 to 2 mm. We carry out SSFDPM (steady state frequency-domain photon migration) measurements using this new probe on the volar forearm and palm of 15 subjects, including five subjects of African descent, five Asians, and five Caucasians. The optical properties of in vivo skin determined using the superficial diffusing probe show considerable similarity to published optical properties of carefully prepared ex vivo epidermis+dermis.