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1.  Non-invasive tissue temperature measurements based on quantitative diffuse optical spectroscopy (DOS) of water 
Physics in Medicine and Biology  2010;55(13):3753-3765.
We describe the development of a non-invasive method for quantitative tissue temperature measurements using Broadband diffuse optical spectroscopy (DOS). Our approach is based on well-characterized opposing shifts in near-infrared (NIR) water absorption spectra that appear with temperature and macromolecular binding state. Unlike conventional reflectance methods, DOS is used to generate scattering-corrected tissue water absorption spectra. This allows us to separate the macromolecular bound water contribution from the thermally induced spectral shift using the temperature isosbestic point at 996 nm. The method was validated in intralipid tissue phantoms by correlating DOS with thermistor measurements (R = 0.96) with a difference of 1.1 ± 0.91 °C over a range of 28–48 °C. Once validated, thermal and hemodynamic (i.e. oxy- and deoxy-hemoglobin concentration) changes were measured simultaneously and continuously in human subjects (forearm) during mild cold stress. DOS-measured arm temperatures were consistent with previously reported invasive deep tissue temperature studies. These results suggest that DOS can be used for non-invasive, co-registered measurements of absolute temperature and hemoglobin parameters in thick tissues, a potentially important approach for optimizing thermal diagnostics and therapeutics.
PMCID: PMC3328132  PMID: 20551502
2.  Imaging in breast cancer: Diffuse optics in breast cancer: detecting tumors in pre-menopausal women and monitoring neoadjuvant chemotherapy 
Breast Cancer Research  2005;7(6):279-285.
Diffuse optical spectroscopy (DOS) and diffuse optical imaging (DOI) are non-invasive diagnostic techniques that employ near-infrared (NIR) light to quantitatively characterize the optical properties of centimeter-thick, multiple-scattering tissues. Although NIR was first applied to breast diaphanography more than 70 years ago, quantitative optical methods employing time- or frequency-domain 'photon migration' technologies have only recently been used for breast imaging. Because their performance is not limited by mammographic density, optical methods can provide new insight regarding tissue functional changes associated with the appearance, progression, and treatment of breast cancer, particularly for younger women and high-risk subjects who may not benefit from conventional imaging methods. This paper reviews the principles of diffuse optics and describes the development of broadband DOS for quantitatively measuring the optical and physiological properties of thick tissues. Clinical results are shown highlighting the sensitivity of diffuse optics to malignant breast tumors in 12 pre-menopausal subjects ranging in age from 30 to 39 years and a patient undergoing neoadjuvant chemotherapy for locally advanced breast cancer. Significant contrast was observed between normal and tumor regions of tissue for deoxy-hemoglobin (p = 0.005), oxy-hemoglobin (p = 0.002), water (p = 0.014), and lipids (p = 0.0003). Tissue hemoglobin saturation was not found to be a reliable parameter for distinguishing between tumor and normal tissues. Optical data were converted into a tissue optical index that decreased 50% within 1 week in response to neoadjuvant chemotherapy. These results suggest a potential role for diffuse optics as a bedside monitoring tool that could aid the development of new strategies for individualized patient care.
PMCID: PMC1410753  PMID: 16457705
3.  Diffuse optical spectroscopy measurements of healing in breast tissue after core biopsy: case study 
Journal of biomedical optics  2009;14(1):014024.
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 37×18×20 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 cm2 area over the biopsied region. A 2-D image of a contrast function called the tissue optical index (TOI=deoxyhemoglobin×water/bulk 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.
PMCID: PMC2872560  PMID: 19256712
near-infrared (NIR); photon migration; tissue spectroscopy; frequency-domain photon migration; breast cancer; hormonal response; menstrual cycle
4.  Non-Invasive In Vivo Characterization of Breast Tumors Using Photon Migration Spectroscopy1 
Neoplasia (New York, N.Y.)  2000;2(1-2):26-40.
Frequency-domain photon migration (FDPM) is a non-invasive optical technique that utilizes intensity-modulated, near-infrared (NIR) light to quantitatively measure optical properties in thick tissues. Optical properties (absorption, µa, and scattering, µs′, parameters) derived from FDPM measurements can be used to construct low-resolution (0.5 to 1 cm) functional images of tissue hemoglobin (total, oxy-, and deoxyforms), oxygen saturation, blood volume fraction, water content, fat content and cellular structure. Unlike conventional NIR transillumination, FDPM enables quantitative analysis of tissue absorption and scattering parameters in a single non-invasive measurement. The unique functional information provided by FDPM makes it well-suited to characterizing tumors in thick tissues. In order to test the sensitivity of FDPM for cancer diagnosis, we have initiated clinical studies to quantitatively determine normal and malignant breast tissue optical and physiological properties in human subjects. Measurements are performed using a non-invasive, multi-wavelength, diode-laser FDPM device optimized for clinical studies. Results show that ductal carcinomas (invasive and in situ) and benign fibroadenomas exhibit 1.25 to 3-fold higher absorption than normal breast tissue. Within this group, absorption is greatest for measurements obtained from sites of invasive cancer. Optical scattering is approximately 20% greater in pre-menopausal versus post-menopausal subjects due to differences in gland/cell proliferation and collagen/fat content. Spatial variations in tissue scattering reveal the loss of differentiation associated with breast disease progression. Overall, the metabolic demands of hormonal stimulation and tumor growth are detectable using photon migration techniques. Measurements provide quantitative optical property values that reflect changes in tissue perfusion, oxygen consumption, and cell/matrix development.
PMCID: PMC1531865  PMID: 10933066
tissue optical properties; absorption; scattering; diffuse optical imaging; near-infrared spectroscopy; hemoglobin; tumor vasculature; extracellular matrix
5.  The Role of Diffuse Optical Spectroscopy in the Clinical Management of Breast Cancer 
Disease Markers  2004;19(2-3):95-105.
Diffuse optical spectroscopy (DOS) of breast tissue provides quantitative, functional information based on optical absorption and scattering properties that cannot be obtained with other radiographic methods. DOS-measured absorption spectra are used to determine the tissue concentrations of deoxyhemoglobin (Hb-R), oxyhemoglobin (Hb-O2), lipid, and water (H2O), as well as to provide an index of tissue hemoglobin oxygen saturation (StO2). Tissue-scattering spectra provide insight into epithelial, collagen, and lipid contributions to breast density. Clinical studies of women with malignant tumors show that DOS is sensitive to processes such as increased tissue vascularization, hypoxia, and edema. In studies of healthy women, DOS detects variations in breast physiology associated with menopausal status, menstrual cycle changes, and hormone replacement. Current research involves using DOS to monitor tumor response to therapy and the co-registration of DOS with magnetic resonance imaging. By correlating DOS-derived parameters with lesion pathology and specific molecular markers, we anticipate that composite “tissue optical indices” can be developed that non-invasively characterize both tumor and normal breast-tissue function.
PMCID: PMC3851626  PMID: 15096707
6.  Spectral discrimination of breast pathologies in situ using spatial frequency domain imaging 
Nationally, 25% to 50% of patients undergoing lumpectomy for local management of breast cancer require a secondary excision because of the persistence of residual tumor. Intraoperative assessment of specimen margins by frozen-section analysis is not widely adopted in breast-conserving surgery. Here, a new approach to wide-field optical imaging of breast pathology in situ was tested to determine whether the system could accurately discriminate cancer from benign tissues before routine pathological processing.
Spatial frequency domain imaging (SFDI) was used to quantify near-infrared (NIR) optical parameters at the surface of 47 lumpectomy tissue specimens. Spatial frequency and wavelength-dependent reflectance spectra were parameterized with matched simulations of light transport. Spectral images were co-registered to histopathology in adjacent, stained sections of the tissue, cut in the geometry imaged in situ. A supervised classifier and feature-selection algorithm were implemented to automate discrimination of breast pathologies and to rank the contribution of each parameter to a diagnosis.
Spectral parameters distinguished all pathology subtypes with 82% accuracy and benign (fibrocystic disease, fibroadenoma) from malignant (DCIS, invasive cancer, and partially treated invasive cancer after neoadjuvant chemotherapy) pathologies with 88% accuracy, high specificity (93%), and reasonable sensitivity (79%). Although spectral absorption and scattering features were essential components of the discriminant classifier, scattering exhibited lower variance and contributed most to tissue-type separation. The scattering slope was sensitive to stromal and epithelial distributions measured with quantitative immunohistochemistry.
SFDI is a new quantitative imaging technique that renders a specific tissue-type diagnosis. Its combination of planar sampling and frequency-dependent depth sensing is clinically pragmatic and appropriate for breast surgical-margin assessment. This study is the first to apply SFDI to pathology discrimination in surgical breast tissues. It represents an important step toward imaging surgical specimens immediately ex vivo to reduce the high rate of secondary excisions associated with breast lumpectomy procedures.
PMCID: PMC3979079  PMID: 23915805
BCS/BCT; Breast-conserving surgery/therapy; Near-infrared spectroscopy; Spatial frequency domain imaging; Diagnostic pathology
7.  Portable, Fiber-Based, Diffuse Reflection Spectroscopy (DRS) Systems for Estimating Tissue Optical Properties 
Applied spectroscopy  2011;62(2):206-215.
Steady-state diffuse reflection spectroscopy is a well-studied optical technique that can provide a noninvasive and quantitative method for characterizing the absorption and scattering properties of biological tissues. Here, we compare three fiber-based diffuse reflection spectroscopy systems that were assembled to create a light-weight, portable, and robust optical spectrometer that could be easily translated for repeated and reliable use in mobile settings. The three systems were built using a broadband light source and a compact, commercially available spectrograph. We tested two different light sources and two spectrographs (manufactured by two different vendors). The assembled systems were characterized by their signal-to-noise ratios, the source-intensity drifts, and detector linearity. We quantified the performance of these instruments in extracting optical properties from diffuse reflectance spectra in tissue-mimicking liquid phantoms with well-controlled optical absorption and scattering coefficients. We show that all assembled systems were able to extract the optical absorption and scattering properties with errors less than 10%, while providing greater than ten-fold decrease in footprint and cost (relative to a previously well-characterized and widely used commercial system). Finally, we demonstrate the use of these small systems to measure optical biomarkers in vivo in a small-animal model cancer therapy study. We show that optical measurements from the simple portable system provide estimates of tumor oxygen saturation similar to those detected using the commercial system in murine tumor models of head and neck cancer.
PMCID: PMC3074566  PMID: 21499501
Optical spectroscopy; Diffuse reflection spectroscopy; DRS; Inverse Monte Carlo; Quantitative physiology; Tissue phantoms; Murine tumors; Spectrometers; Cancer
8.  Spectral tomography with diffuse near-infrared light: inclusion of broadband frequency domain spectral data 
Journal of biomedical optics  2008;13(4):041305.
Near-infrared (NIR) region-based spectroscopy is examined for accuracy with spectral recovery using frequency domain data at a discrete number of wavelengths, as compared to that with broadband continuous wave data. Data with more wavelengths in the frequency domain always produce superior quantitative spectroscopy results with reduced noise and error in the chromophore concentrations. Performance of the algorithm in the situation of doing region-guided spectroscopy within the MRI is also considered, and the issue of false positive prior regions being identified is examined to see the effect of added wavelengths. The results indicate that broadband frequency domain data are required for maximal accuracy. A broadband frequency domain experimental system was used to validate the predictions, using a mode-locked Ti:sapphire laser for the source between 690- and 850-nm wavelengths. The 80-MHz pulsed signal is heterodyned with photomultiplier tube detection, to lower frequency for data acquisition. Tissue-phantom experiments with known hemoglobin absorption and tissue-like scatter values are used to validate the system, using measurements every 10 nm. More wavelengths clearly provide superior quantification of total hemoglobin values. The system and algorithms developed here should provide an optimal way to quantify regions with the goal of image-guided breast tissue spectroscopy within the MRI.
PMCID: PMC3018156  PMID: 19021313
frequency domain; region-guided spectroscopy; spectral tomography; near infrared
9.  Scatter spectroscopic imaging distinguishes between breast pathologies in tissues relevant to surgical margin assessment 
A new approach to spectroscopic imaging was developed to detect and discriminate microscopic pathologies in resected breast tissues; diagnostic performance of the prototype system was tested in 27 tissues procured during breast conservative surgery.
Experimental Design
A custom-built, scanning in situ spectroscopy platform sampled broadband reflectance from a 150μm diameter spot over a 1×1cm2 field using a dark field geometry and telecentric lens; the system was designed to balance sensitivity to cellular morphology and imaging the inherent diversity within tissue subtypes. Nearly 300,000 broadband spectra were parameterized using light scattering models and spatially dependent spectral signatures were interpreted using a co-occurrence matrix representation of image texture.
Local scattering changes distinguished benign from malignant pathologies with 94% accuracy, 93% sensitivity, 95% specificity, and 93% positive & 95% negative predictive values using a threshold-based classifier. Texture and shape features were important to optimally discriminate benign from malignant tissues, including pixel-to-pixel correlation, contrast and homogeneity, and the shape features of fractal dimension and Euler number. Analysis of the region-based diagnostic performance showed that spectroscopic image features from 1×1mm2 areas were diagnostically discriminant and enabled quantification of within-class tissue heterogeneities.
Localized scatter-imaging signatures detected by the scanning spectroscopy platform readily distinguished benign from malignant pathologies in surgical tissues and demonstrated new spectral-spatial signatures of clinical breast pathologies.
PMCID: PMC3500421  PMID: 22908098
Spectroscopy; imaging; light scattering; pathology; breast conserving surgery; texture; morphology
10.  Dependence on NIRS Source-Detector Spacing of Cytochrome c Oxidase Response to Hypoxia and Hypercapnia in the Adult Brain 
Transcranial near-infrared spectroscopy (NIRS) provides an assessment of cerebral oxygen metabolism by monitoring concentration changes in oxidised cytochrome c oxidase Δ[oxCCO]. We investigated the response of Δ[oxCCO] to global changes in cerebral oxygen delivery at different source-detector separations in 16 healthy adults. Hypoxaemia was induced by delivery of a hypoxic inspired gas mix and hypercapnia by addition of 6 % CO2 to the inspired gases. A hybrid optical spectrometer was used to measure frontal cortex light absorption and scattering at discrete wavelengths and broadband light attenuation at 20, 25, 30 and 35 mm. Without optical scattering changes, a decrease in cerebral oxygen delivery, resulting from the reduction in arterial oxygen saturation during hypoxia, led to a decrease in Δ[oxCCO]. In contrast, Δ[oxCCO] increased when cerebral oxygen delivery increased due to increased cerebral blood flow during hypercapnia. In both cases the magnitude of the Δ[oxCCO] response increased from the detectors proximal (measuring superficial tissue layers) to the detectors distal (measuring deep tissue layers) to the broadband light source. We conclude that the Δ[oxCCO] response to hypoxia and hypercapnia appears to be dependent on penetration depth, possibly reflecting differences between the intra- and extracerebral tissue concentration of cytochrome c oxidase.
PMCID: PMC4037984  PMID: 23852515
11.  Accurate optical parameter extraction procedure for broadband near-infrared spectroscopy of brain matter 
Journal of Biomedical Optics  2013;18(1):017008.
Modeling behavior of broadband (30 to 1000 MHz) frequency modulated near-infrared (NIR) photons through a phantom is the basis for accurate extraction of optical absorption and scattering parameters of biological turbid media. Photon dynamics in a phantom are predicted using both analytical and numerical simulation and are related to the measured insertion loss (IL) and insertion phase (IP) for a given geometry based on phantom optical parameters. Accuracy of the extracted optical parameters using finite element method (FEM) simulation is compared to baseline analytical calculations from the diffusion equation (DE) for homogenous brain phantoms. NIR spectroscopy is performed using custom-designed, broadband, free-space optical transmitter (Tx) and receiver (Rx) modules that are developed for photon migration at wavelengths of 680, 780, and 820 nm. Differential detection between two optical Rx locations separated by 0.3 cm is employed to eliminate systemic artifacts associated with interfaces of the optical Tx and Rx with the phantoms. Optical parameter extraction is achieved for four solid phantom samples using the least-square-error method in MATLAB (for DE) and COMSOL (for FEM) simulation by fitting data to measured results over broadband and narrowband frequency modulation. Confidence in numerical modeling of the photonic behavior using FEM has been established here by comparing the transmission mode’s experimental results with the predictions made by DE and FEM for known commercial solid brain phantoms.
PMCID: PMC3545521  PMID: 23322361
functional near-infrared; traumatic brain injury; finite element method; diffusion equation; COMSOL; optical transmitter; optical receiver; tri-wavelength; continuous wave; time domain; frequency domain; photon density wave; vertical cavity surface emitting laser; insertion loss; insertion phase
12.  Investigation of spectral interferences on the accuracy of broadband CW-NIRS tissue SO2 determination 
Biomedical Optics Express  2010;1(3):748-761.
An accurate SO2 prediction method for using broadband continuous-wave diffuse reflectance near infrared (NIR) spectroscopy is proposed. The method fitted the NIR spectra to a Taylor expansion attenuation model, and used the simulated annealing method to initialize the nonlinear least squares fit. This paper investigated the effect of potential spectral interferences that are likely to be encountered in clinical use, on SO2 prediction accuracy. The factors include the concentration of hemoglobin in blood, the volume of blood and volume of water in the tissue under the sensor, reduced scattering coefficient, µs', of the muscle, fat thickness and the source-detector spacing. The SO2 prediction method was evaluated on simulated muscle spectra as well as on dual-dye phantoms which simulate the absorbance of oxygenated and deoxygenated hemoglobin.
PMCID: PMC3018045  PMID: 21258506
(170.0170) Medical optics and biotechnology; (170.1470) Blood/tissue constituent monitoring; (170.6510) Spectroscopy, tissue diagnostics; Muscle oxygen saturation measurement; Simulated annealing
13.  Test of Multi-spectral Vegetation Index for Floating and Canopy-forming Submerged Vegetation 
Remote sensing of terrestrial vegetation has been successful thanks to the unique spectral characteristics of green vegetation, low reflectance in red and high reflectance in Near-InfraRed (NIR). These spectral characteristics were used to develop vegetation indices, including Normalized Difference Vegetation Index (NDVI). However, the NIR absorption by water and light scattering from suspended particles reduces the practical application of such indices in aquatic vegetation studies, especially for the Submerged Aquatic Vegetation (SAV) that grows below water surface. We experimentally tested if NDVI can be used to depict canopies of aquatic plants in shallow waters. A 100-gallon-outdoor tank was lined with black pond liners, a black panel or SAV shoots were mounted on the bottom, and filled with water up to 0.5 m. We used a GER 1500 spectroradiometer to collect spectral data over floating waterhyacinth (Eichhornia crassipes) and also over the tanks that contain SAV and black panel at varying water depths. The measured upwelling radiance was converted to % reflectance; and we integrated the hyperspectral reflectance to match the Red and NIR bands of three satellite sensors: Landsat 7 ETM, SPOT 5 HRG, and ASTER. NDVI values ranged 0.6–0.65 when the SAV canopy was at the water level, then they decreased linearly (slope of 0.013 NDVI/meter) with water depth increases in clear water. When corrected for water attenuation using the data obtained from the black panel, the NDVI values significantly increased at all depths that we tested (0.1 – 0.5 m). Our results suggest the conventional NDVI: (1) can be used to depict SAV canopies at water surface; (2) is not a good indicator for SAV that is adapted to live underwater or other aquatic plants that are submerged during flooding even at shallow waters (0.3 m); and (3) the index values can significantly improve if information on spectral reflectance attenuation caused by water volume increases is collected simultaneously through ground-truthing and integrated.
PMCID: PMC3700010  PMID: 19151445
Vegetation Index; NDVI; hyperspectral; SAV; water depth
14.  Broadband diffuse optical spectroscopy assessment of hemorrhage- and hemoglobin-based blood substitute resuscitation 
Journal of biomedical optics  2009;14(4):044027.
Hemoglobin-based oxygen carriers (HBOCs) are solutions of cell-free hemoglobin (Hb) that have been developed for replacement or augmentation of blood transfusion. It is important to monitor in vivo tissue hemoglobin content, total tissue hemoglobin [THb], oxy- and deoxy-hemoglobin concentrations ([OHb], [RHb]), and tissue oxygen saturation (StO2=[OHb]/[THb]×100%) to evaluate effectiveness of HBOC transfusion. We designed and constructed a broadband diffuse optical spectroscopy (DOS) prototype system to measure bulk tissue absorption and scattering spectra between 650 and 1000 nm capable of accurately determining these tissue hemoglobin component concentrations in vivo. Our purpose was to assess the feasibility of using DOS to optically monitor tissue [OHb], [RHb], StO2, and total tissue hemoglobin concentration ([THb]=[OHb]+[RHb]) during HBOC infusion using a rabbit hypovolemic shock model. The DOS prototype probe was placed on the shaved inner thigh muscle of the hind leg to assess concentrations of [OHb], [RHb], [THb], as well as StO2. Hemorrhagic shock was induced in intubated New Zealand white rabbits (N=6) by withdrawing blood via a femoral arterial line to 20% blood loss (10–15 cc/kg). Hemoglobin glutamer-200 (Hb-200) 1:1 volume resuscitation was administered following the hemorrhage. These values were compared against traditional invasive measurements, serum hemoglobin concentration (sHGB), systemic blood pressure, heart rate, and blood gases. DOS revealed increases of [THb], [OHb], and tissue hemoglobin oxygen saturation after Hb-200 infusion, while blood total hemoglobin values continued did not increase; we speculate, due to hyperosmolality induced hemodilution. DOS enables noninvasive in vivo monitoring of tissue hemoglobin and oxygenation parameters during shock and volume expansion with HBOC and potentially enables the assessment of efficacy of resuscitation efforts using artificial blood substitutes.
PMCID: PMC2868523  PMID: 19725738
hemorrhagic shock; blood substitute; diffuse optical spectroscopy
15.  Investigation of the impact of water absorption on retinal OCT imaging in the 1060 nm range 
Biomedical Optics Express  2012;3(7):1620-1631.
Recently, the wavelength range around 1060 nm has become attractive for retinal imaging with optical coherence tomography (OCT), promising deep penetration into the retina and the choroid. The adjacent water absorption bands limit the useful bandwidth of broadband light sources, but until now, the actual limitation has not been quantified in detail. We have numerically investigated the impact of water absorption on the axial resolution and signal amplitude for a wide range of light source bandwidths and center wavelengths. Furthermore, we have calculated the sensitivity penalty for maintaining the optimal resolution by spectral shaping. As our results show, with currently available semiconductor-based light sources with up to 100–120 nm bandwidth centered close to 1060 nm, the resolution degradation caused by the water absorption spectrum is smaller than 10%, and it can be compensated by spectral shaping with negligible sensitivity penalty. With increasing bandwidth, the resolution degradation and signal attenuation become stronger, and the optimal operating point shifts towards shorter wavelengths. These relationships are important to take into account for the development of new broadband light sources for OCT.
PMCID: PMC3395486  PMID: 22808433
(170.4500) Optical coherence tomography; (170.4460) Ophthalmic optics and devices; (350.5730) Resolution
16.  Intrinsic Near-Infrared Spectroscopic Markers of Breast Tumors 
Disease markers  2009;25(6):281-290.
We have discovered quantitative optical biomarkers unique to cancer by developing a double-differential spectroscopic analysis method for near-infrared (NIR, 650–1000 nm) spectra acquired non-invasively from breast tumors. These biomarkers are characterized by specific NIR absorption bands. The double-differential method removes patient specific variations in molecular composition which are not related to cancer, and reveals these specific cancer biomarkers. Based on the spectral regions of absorption, we identify these biomarkers with lipids that are present in tumors either in different abundance than in the normal breast or new lipid components that are generated by tumor metabolism. Furthermore, the O-H overtone regions (980–1000 nm) show distinct variations in the tumor as compared to the normal breast. To quantify spectral variation in the absorption bands, we constructed the Specific Tumor Component (STC) index. In a pilot study of 12 cancer patients we found 100% sensitivity and 100% specificity for lesion identification. The STC index, combined with other previously described tissue optical indices, further improves the diagnostic power of NIR for breast cancer detection.
PMCID: PMC2732199  PMID: 19208946
Breast cancer; optical spectra; Near Infrared Spectroscopy (NIRS) lipids; lipid spectroscopy
17.  Intrinsic near-infrared spectroscopic markers of breast tumors 
Disease markers  2008;25(6):281-290.
We have discovered quantitative optical biomarkers unique to cancer by developing a double-differential spectroscopic analysis method for near-infrared (NIR, 650-1000nm) spectra acquired non-invasively from breast tumors. These biomarkers are characterized by specific NIR absorption bands. The double-differential method removes patient specific variations in molecular composition which are not related to cancer, and reveals these specific cancer biomarkers. Based on the spectral regions of absorption, we identify these biomarkers with lipids that are present in tumors either in different abundance than in the normal breast or new lipid components that are generated by tumor metabolism. Furthermore, the O-H overtone regions (980-1000 nm) show distinct variations in the tumor as compared to the normal breast. To quantify spectral variation in the absorption bands, we constructed the Specific Tumor Component (STC) index. In a pilot study of 12 cancer patients we found 100% sensitivity and 100% specificity for lesion identification. The STC index, combined with other previously described tissue optical indices, further improves the diagnostic power of NIR for breast cancer detection.
PMCID: PMC2732199  PMID: 19208946
Breast Cancer; Optical Spectra; Near Infrared Spectroscopy (NIRS) Lipids; Lipid Spectroscopy
18.  Pilot clinical study for quantitative spectral diagnosis of non-melanoma skin cancer 
Lasers in surgery and medicine  2010;42(10):716-727.
Several research groups have demonstrated the non-invasive diagnostic potential of diffuse optical spectroscopy (DOS) and laser-induced fluorescence (LIF) techniques for early cancer detection. By combining both modalities, one can simultaneously measure quantitative parameters related to the morphology, function and biochemical composition of tissue and use them to diagnose malignancy. The objective of this study was to use a quantitative reflectance/fluorescence spectroscopic technique to determine the optical properties of normal skin and non-melanoma skin cancers and the ability to accurately classify them. An additional goal was to determine the ability of the technique to differentiate non-melanoma skin cancers from normal skin.
Study Design
The study comprised 48 lesions measured from 40 patients scheduled for a biopsy of suspected non-melanoma skin cancers. White light reflectance and laser-induced fluorescence spectra (wavelength range = 350–700 nm) were collected from each suspected lesion and adjacent clinically normal skin using a custom-built, optical fiber-based clinical instrument. After measurement, the skin sites were biopsied and categorized according to histopathology. Using a quantitative model, we extracted various optical parameters from the measured spectra that could be correlated to the physiological state of tissue.
Scattering from cancerous lesions was significantly lower than normal skin for every lesion group, whereas absorption parameters were significantly higher. Using numerical cut-offs for our optical parameters, our clinical instrument could classify basal cell carcinomas with a sensitivity and specificity of 94 and 89%, respectively. Similarly, the instrument classified actinic keratoses and squamous cell carcinomas with a sensitivity of 100% and specificity of 50%.
The measured optical properties and fluorophore contributions of normal skin and non-melanoma skin cancers are significantly different from each other and correlate well with tissue pathology. A diagnostic algorithm that combines these extracted properties holds promise for the potential non-invasive diagnosis of skin cancer.
PMCID: PMC3059518  PMID: 21246575
Optical spectroscopy; optical properties; non-invasive diagnosis
19.  Quantification in tissue near-infrared spectroscopy 
In near-infrared spectroscopy (NIRS) of tissue, light attenuation is due to: (i) absorption from chromophores of fixed concentration, (ii) absorption from chromophores of variable concentration, and (iii) light scatter. NIRS is usually concerned with trying to quantify the concentrations of chromophores in category (ii), in particular oxy- and deoxyhaemoglobin (HbO2 and Hb) and cytochrome oxidase.
In the absence of scatter the total light absorption in the medium is a linear sum of that due to each chromophore. In a scattering medium like tissue, this linear summation is distorted because the optical path length at each wavelength may differ. This distorted spectrum is then superimposed upon a further wavelength-dependent attenuation arising from light loss due to scatter, which is a complex function of the tissue absorption and scattering coefficients ( μa and μs), scattering phase function, and tissue and measurement geometry. Consequently, quantification of NIRS data is difficult.
Over the past 20 years many differing approaches to quantification have been tried. The development of methods for measuring optical path length in tissue initially enabled changes in concentration to be quantified, and subsequently methods for absolute quantification of HbO2 and Hb were developed by correlating NIRS changes with an independent measurement of arterial haemoglobin saturation. Absolute determination of tissue optical properties, however, requires additional information over and above the detected intensity at the tissue surface, which must then be combined with a model of light transport to derive μa and μs. The additional data can take many forms, e.g. the change in intensity with distance, the temporal dispersion of light from an ultrashort input light pulse, or phase, and modulation depth changes of intensity-modulated light. All these approaches are now being actively pursued with considerable success. However, all the approaches are limited by the accuracy of the light transport models, especially in inhomogeneous media.
PMCID: PMC1691964
Continuous Intensity Spectrometer Intensity Modulated Spectrometer Time Resolved Spectrometer Absolute Quantification Light Distribution
20.  Wavelength band optimization in spectral near-infrared optical tomography improves accuracy while reducing data acquisition and computational burden 
Journal of biomedical optics  2008;13(5):054037.
Multispectral near-infrared (NIR) tomographic imaging has the potential to provide information about molecules absorbing light in tissue, as well as subcellular structures scattering light, based on transmission measurements. However, the choice of possible wavelengths used is crucial for the accurate separation of these parameters, as well as for diminishing crosstalk between the contributing chromophores. While multispectral systems are often restricted by the wavelengths of laser diodes available, continuous-wave broadband systems exist that have the advantage of providing broadband NIR spectroscopy data, albeit without the benefit of the temporal data. In this work, the use of large spectral NIR datasets is analyzed, and an objective function to find optimal spectral ranges (windows) is examined. The optimally identified wavelength bands derived from this method are tested using both simulations and experimental data. It is found that the proposed method achieves images as qualitatively accurate as using the full spectrum, but improves crosstalk between parameters. Additionally, the judicious use of these spectral windows reduces the amount of data needed for full spectral tomographic imaging by 50%, therefore increasing computation time dramatically.
PMCID: PMC3801165  PMID: 19021417
iomedical optics; image reconstruction; inverse problems
21.  Galactosyl Human Serum Albumin-NMP1 Conjugate: A Near Infrared (NIR)-Activatable Fluorescence Imaging Agent to Detect Peritoneal Ovarian Cancer Metastases 
Bioconjugate chemistry  2012;23(8):1671-1679.
Patient survival depends on the completeness of resection of peritoneal ovarian cancer metastases (POCM) and therefore, it is important to develop methods to enhance detection. Previous probe designs based on activatable galactosyl human serum albumin (hGSA)-fluorophore pairs, which target lectin receptors expressed on POCM, have used only visible range dyes conjugated to hGSA. However, imaging probes emitting fluorescence in the NIR range are advantageous because NIR photons have deeper in vivo tissue penetration and result in lower background autofluorescence than those emitting in the visible range. A NIR-activatable hGSA fluorophore was synthesized using a bacteriochlorin-based dye, NMP1. NMP1 has two unique absorption peaks, one in the green range and the other in the NIR range, but emits at a NIR peak of 780 nm. NMP1, thus, has two different Stokes shifts that have the potential to allow imaging of POCM both at the peritoneal surface and just below it.
hGSA was conjugated with 2 NMP1 molecules to create a self-quenching complex (hGSA-NMP1). The activation ratio of hGSA-NMP1 was measured by the fluorescence intensity before and after exposure to 10% SDS. The activation ratio of hGSA-NMP1 was ~100-fold in vitro. Flow cytometry, fluorescence microscopy, and in vivo spectral fluorescence imaging were carried out to compare hGSA-NMP1 with hGSA-IR800 and hGSA-ICG (two always-on control agents with similar emission to NMP1) in terms of comparative fluorescence signal and the ability to detect POCM in mice models. The sensitivity and specificity of hGSA-NMP1 for POCM implant detection were determined by co-localizing NMP1 emission spectra with red fluorescent protein (RFP) expressed constitutively in SHIN3 tumor implants at different depths below the peritoneal surface. In vitro, SHIN3 cells were easily detectable after 3 hours of incubation with hGSA-NMP1. In vivo submillimeter POCM foci were clearly detectable with spectral fluorescence imaging using hGSA-NMP1. Among 555 peritoneal lesions, hGSA-NMP, using NIR and green excitation light, respectively, detect 75% of all lesions and 91% of lesions ~0.8 mm or greater in diameter. Few false positives were encountered. Nodules located at a depth below the small bowel surface were only depicted with hGSA-NMP1.
We conclude that hGSA-NMP1 is useful in imaging peritoneal ovarian cancer metastases, located both superficially and deep in the abdominal cavity.
PMCID: PMC3432315  PMID: 22799539
fluorescence imaging; activatable; near infrared; multiple excitations
22.  Diagnostic potential of near-infrared Raman spectroscopy in the stomach: differentiating dysplasia from normal tissue 
British Journal of Cancer  2008;98(2):457-465.
Raman spectroscopy is a molecular vibrational spectroscopic technique that is capable of optically probing the biomolecular changes associated with diseased transformation. The purpose of this study was to explore near-infrared (NIR) Raman spectroscopy for identifying dysplasia from normal gastric mucosa tissue. A rapid-acquisition dispersive-type NIR Raman system was utilised for tissue Raman spectroscopic measurements at 785 nm laser excitation. A total of 76 gastric tissue samples obtained from 44 patients who underwent endoscopy investigation or gastrectomy operation were used in this study. The histopathological examinations showed that 55 tissue specimens were normal and 21 were dysplasia. Both the empirical approach and multivariate statistical techniques, including principal components analysis (PCA), and linear discriminant analysis (LDA), together with the leave-one-sample-out cross-validation method, were employed to develop effective diagnostic algorithms for classification of Raman spectra between normal and dysplastic gastric tissues. High-quality Raman spectra in the range of 800–1800 cm−1 can be acquired from gastric tissue within 5 s. There are specific spectral differences in Raman spectra between normal and dysplasia tissue, particularly in the spectral ranges of 1200–1500 cm−1 and 1600–1800 cm−1, which contained signals related to amide III and amide I of proteins, CH3CH2 twisting of proteins/nucleic acids, and the C=C stretching mode of phospholipids, respectively. The empirical diagnostic algorithm based on the ratio of the Raman peak intensity at 875 cm−1 to the peak intensity at 1450 cm−1 gave the diagnostic sensitivity of 85.7% and specificity of 80.0%, whereas the diagnostic algorithms based on PCA-LDA yielded the diagnostic sensitivity of 95.2% and specificity 90.9% for separating dysplasia from normal gastric tissue. Receiver operating characteristic (ROC) curves further confirmed that the most effective diagnostic algorithm can be derived from the PCA-LDA technique. Therefore, NIR Raman spectroscopy in conjunction with multivariate statistical technique has potential for rapid diagnosis of dysplasia in the stomach based on the optical evaluation of spectral features of biomolecules.
PMCID: PMC2361456  PMID: 18195711
dysplasia; near-infrared Raman spectroscopy; optical diagnosis; stomach; principal components analysis; linear discriminant analysis
23.  Impact of Tissue Heterogeneity on Noninvasive Near-Infrared Glucose Measurements in Interstitial Fluid of Rat Skin 
Movement of the optical interface used to collect noninvasive near-infrared spectra is known to dramatically increase prediction errors for glucose concentration measurements within the interstitial fluid of living rat skin. Prediction errors increase by more than 2.5-fold when the interface is moved before each non-invasive measurement compared to measurements where the interface position is constant throughout. Chemical heterogeneity of the skin matrix is examined as a possible mechanism for the strong sensitivity to the interface placement during noninvasive measurements conducted from transmission near-infrared absorption spectroscopy.
Microspectroscopy was performed over a region of the near-infrared spectrum (4000–5000 cm−1) to map the concentrations of water, collagen protein, fat, and keratin protein within the skin tissue matrix through which noninvasive spectra are collected. Maps were created for multiple samples of skin excised from male and female animals. Sets of near-infrared spectra were constructed to simulate noninvasive spectra in accord with the basic tissue composition found from the microspectroscopic maps with added information corresponding to a span of glucose concentrations ranging from 5 to 35 mM and Gaussian-distributed noise.
Microspectroscopic maps of rat skin reveal similar patterns of heterogeneity for major chemical components of skin samples excised from both male and female animals. These maps demonstrate concentration domains with dimensions similar to the size of the fiber interface used to collect noninvasive spectra. Partial least squares calibration models generated from sets of simulated spectra demonstrate increases in prediction errors for glucose when the spectral matrix is changed in accord with the degree of chemical heterogeneity displayed in the skin maps. Prediction errors typically increase between 100 and 1000% when comparing errors generated from spectra that represent a single tissue composition versus spectra that represent a varied skin composition in accord with the distribution displayed in the skin maps.
The distribution of the major components of skin is not uniform, but establishes domains within the skin matrix that strongly impact prediction errors for the noninvasive spectroscopic measurement of glucose within the interstitial fluid of rat dermis tissue. The observed increase in prediction error (>2.5-fold) determined from actual noninvasive measurements is within the lower range of prediction error increases demonstrated by this simulation study. These findings implicate that chemical heterogeneity within the tissue matrix is a major factor in the sensitivity of the location of the fiber interface used to collect noninvasive spectral data.
PMCID: PMC2956801  PMID: 20920424
interstitial fluid; microspectroscopic mapping; near-infrared spectroscopy; noninvasive glucose sensing; partial least squares regression; skin heterogeneity
24.  Multispectral near-IR reflectance and transillumination imaging of teeth 
Biomedical Optics Express  2011;2(10):2804-2814.
NIR imaging methods do not require ionizing radiation and have great potential for detecting caries lesions (tooth decay) on high-risk proximal and occlusal tooth surfaces and at the earliest stages of development. Previous in vitro and in vivo studies at 1300-nm demonstrated that high contrast reflectance and transillumination images could be acquired of caries lesions on tooth proximal and occlusal surfaces where most new decay is found. Water absorption varies markedly between 1200 and 1600-nm and the scattering properties of enamel and the underlying dentin have not been characterized in this region. Hyperspectral reflectance studies show lower reflectivity from sound enamel and dentin at NIR wavelengths with higher water absorption. The purpose of this imaging study was to determine which NIR wavelengths between 1200 and 1600-nm provide the highest contrast of demineralization or caries lesions for each of the different modes of NIR imaging, including transillumination of proximal and occlusal surfaces along with cross polarization reflectance measurements. A tungsten halogen lamp with several spectral filters and a Ge-enhanced CMOS focal plane array (FPA) sensitive from 400 to 1600-nm were used to acquire the images of caries lesions on extracted teeth. Artificial interproximal lesions were created on twelve tooth sections of 5 & 6-mm thickness that were used for transillumination imaging. Fifty-four extracted teeth with suspected occlusal lesions were also examined in both occlusal transillumination and reflectance imaging modes. Cavity preparations were also cut into whole teeth and filled with composite and used to compare the contrast between composite and enamel at NIR wavelengths. NIR wavelengths longer than 1400-nm are likely to have better performance for the transillumination of occlusal caries lesions while 1300-nm appears best for the transillumination of proximal surfaces. Loss of mobile water in enamel markedly reduced the transparency of the enamel at all NIR wavelengths. Significantly higher contrast was attained for reflectance measurements at wavelengths that have higher water absorption, namely 1460-nm. Wavelengths with higher water absorption also provided higher contrast of composite restorations.
PMCID: PMC3191447  PMID: 22025986
(110.0113) Imaging through turbid media; (170.1850) Dentistry
25.  Optical imaging correlates with magnetic resonance imaging breast density and reveals composition changes during neoadjuvant chemotherapy 
In addition to being a risk factor for breast cancer, breast density has been hypothesized to be a surrogate biomarker for predicting response to endocrine-based chemotherapies. The purpose of this study was to evaluate whether a noninvasive bedside scanner based on diffuse optical spectroscopic imaging (DOSI) provides quantitative metrics to measure and track changes in breast tissue composition and density. To access a broad range of densities in a limited patient population, we performed optical measurements on the contralateral normal breast of patients before and during neoadjuvant chemotherapy (NAC). In this work, DOSI parameters, including tissue hemoglobin, water, and lipid concentrations, were obtained and correlated with magnetic resonance imaging (MRI)-measured fibroglandular tissue density. We evaluated how DOSI could be used to assess breast density while gaining new insight into the impact of chemotherapy on breast tissue.
This was a retrospective study of 28 volunteers undergoing NAC treatment for breast cancer. Both 3.0-T MRI and broadband DOSI (650 to 1,000 nm) were obtained from the contralateral normal breast before and during NAC. Longitudinal DOSI measurements were used to calculate breast tissue concentrations of oxygenated and deoxygenated hemoglobin, water, and lipid. These values were compared with MRI-measured fibroglandular density before and during therapy.
Water (r = 0.843; P < 0.001), deoxyhemoglobin (r = 0.785; P = 0.003), and lipid (r = -0.707; P = 0.010) concentration measured with DOSI correlated strongly with MRI-measured density before therapy. Mean DOSI parameters differed significantly between pre- and postmenopausal subjects at baseline (water, P < 0.001; deoxyhemoglobin, P = 0.024; lipid, P = 0.006). During NAC treatment measured at about 90 days, significant reductions were observed in oxyhemoglobin for pre- (-20.0%; 95% confidence interval (CI), -32.7 to -7.4) and postmenopausal subjects (-20.1%; 95% CI, -31.4 to -8.8), and water concentration for premenopausal subjects (-11.9%; 95% CI, -17.1 to -6.7) compared with baseline. Lipid increased slightly in premenopausal subjects (3.8%; 95% CI, 1.1 to 6.5), and water increased slightly in postmenopausal subjects (4.4%; 95% CI, 0.1 to 8.6). Percentage change in water at the end of therapy compared with baseline correlated strongly with percentage change in MRI-measured density (r = 0.864; P = 0.012).
DOSI functional measurements correlate with MRI fibroglandular density, both before therapy and during NAC. Although from a limited patient dataset, these results suggest that DOSI may provide new functional indices of density based on hemoglobin and water that could be used at the bedside to assess response to therapy and evaluate disease risk.
PMCID: PMC3672664  PMID: 23433249

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