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ABSTRACT: We applied a visible-light spectroscopic optical coherence tomography (vis-OCT) for in vivo retinal oximetry. To extract hemoglobin oxygen saturation (sO<sub>2</sub>) in individual retinal vessels, we established a comprehensive analytical model to describe optical absorption, optical scattering, and blood cell packing factor in the whole blood and fit the acquired vis-OCT signals from the bottom of each imaged vessel. We found that averaged sO<sub>2</sub> values in arterial and venous bloods were 95% and 72%, respectively.
Optics Letters 06/2013; 38(11):1796-8. · 3.40 Impact Factor
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ABSTRACT: Exploration of nanoscale tissue structures is crucial in understanding biological processes. Although novel optical microscopy methods have been developed to probe cellular features beyond the diffraction limit, nanometer-scale quantification remains still inaccessible for in situ tissue. Here we demonstrate that, without actually resolving specific geometrical feature, OCT can be sensitive to tissue structural properties at the nanometer length scale. The statistical mass-density distribution in tissue is quantified by its autocorrelation function modeled by the Whittle-Mateŕn functional family. By measuring the wavelength-dependent backscattering coefficient μb(λ) and the scattering coefficient μs, we introduce a technique called inverse spectroscopic OCT (ISOCT) to quantify the mass-density correlation function. We find that the length scale of sensitivity of ISOCT ranges from ~30 to ~450 nm. Although these sub-diffractional length scales are below the spatial resolution of OCT and therefore not resolvable, they are nonetheless detectable. The sub-diffractional sensitivity is validated by 1) numerical simulations; 2) tissue phantom studies; and 3) ex vivo colon tissue measurements cross-validated by scanning electron microscopy (SEM). Finally, the 3D imaging capability of ISOCT is demonstrated with ex vivo rat buccal and human colon samples.
Optics Express 04/2013; 21(7):9043-59. · 3.59 Impact Factor
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ABSTRACT: Ovarian cancer ranks fifth in cancer fatalities among American women. Although curable at early stages with surgery, most women are diagnosed with symptoms of late-stage metastatic disease. Moreover, none of the current diagnostic techniques are clinically recommended for at-risk women as they preferentially target low-grade tumors (which do not affect longevity) and fail to capture early signatures of more lethal serous tumors which originate in the fimbrae region of the fallopian tubes. Hence, the early detection of ovarian cancer is challenging given the current strategy. Recently, our group has developed a novel optical imaging technique, partial wave spectroscopic (PWS) microscopy, that can quantify the nanoscale macromolecular density fluctuations within biological cells via a biomarker, disorder strength (L(d) ). Using the concept of field carcinogenesis, we propose a method of detecting ovarian cancer by PWS assessment of endometrial and endocervical columnar cells. The study includes 26 patients (controls = 15, cancer = 11) for endometrium and 23 (controls = 13, cancer = 10) for endocervix. Our results highlight a significant increase in L(d) (% fold-increase > 50%, P-value < 0.05) for columnar epithelial cells obtained from cancer patients compared to controls for both endocervix and endometrium. Overall, the quantification of field carcinogenic events in the endometrium and the novel observation of its extension to the cervix are unique findings in the understanding of ovarian field carcinogenesis. We further show independent validation of the presence of cervical field carcinogenesis with mico-RNA expression data. © 2013 Wiley Periodicals, Inc.
International Journal of Cancer 02/2013; · 5.44 Impact Factor
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ABSTRACT: Several optical techniques and fiber-optic probe systems have been designed to measure the optical properties of tissue. While a wide range of options is often beneficial, it poses a problem to investigators selecting which method to use for their biomedical application of interest. We present a methodology to optimally select a probe that matches the application requirements. Our method is based both on matching a probe's mean sampling depth with the optimal diagnostic depth of the clinical application and on choosing a probe whose interrogation depth and path length is the least sensitive to alterations in the target medium's optical properties. Satisfying these requirements ensures that the selected probe consistently assesses the relevant tissue volume with minimum variability. To aid in probe selection, we have developed a publicly available graphical user interface that takes the desired sampling depth and optical properties of the medium as its inputs and automatically ranks different techniques in their ability to robustly target the desired depth. Techniques investigated include single fiber spectroscopy, differential path length spectroscopy, polarization-gating, elastic light scattering spectroscopy, and diffuse reflectance. The software has been applied to biological case studies.
Journal of Biomedical Optics 02/2013; 18(2):27012. · 3.16 Impact Factor
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IEEE Transactions on Antennas and Propagation 02/2013; 61(2):818. · 2.15 Impact Factor
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ABSTRACT: We demonstrate how a tightly-focused coherent TEMmn laser beam can be computed in the finite-difference time-domain (FDTD) method. The electromagnetic field around the focus is decomposed into a plane-wave spectrum, and approximated by a finite number of plane waves injected into the FDTD grid using the total-field/scattered-field (TF/SF) method. We provide an error analysis, and guidelines for the discrete approximation. We analyze the scattering of the beam from layered spaces and individual scatterers. The described method should be useful for the simulation of confocal microscopy and optical data storage. An implementation of the method can be found in our free and open source FDTD software ("Angora").
Optics Express 01/2013; 21(1):87-101. · 3.59 Impact Factor
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ABSTRACT: We previously reported the utility of Low-Coherence Enhanced Backscattering (LEBS) Spectroscopy in detecting optical changes in uninvolved rectal mucosa, changes that are indicative of the presence of advanced colorectal adenomas elsewhere in the colon (field carcinogenesis). We hypothesized that the alterations in optical signatures are due to structural changes in colonocytes. To elucidate those colonocyte changes, we used LEBS and an early time point in an animal model of colorectal field carcinogenesis - rats treated with azoxymethane (AOM). Changes in LEBS markers in intact mucosa from AOM-treated rats could be at least partially attributed to changes in colonocytes. To investigate the molecular mechanisms underlying the colonocyte abnormalities in premalignant colon, we took a candidate approach. We compared expression profiles of genes implicated directly or indirectly in cytoskeletal dysregulation in colorectal tissues from saline-treated versus AOM-treated rats. Our data suggest that a number of genes known to affect colon tumorigenesis are up-regulated in colonocytes, and genes previously reported to be tumor suppressors in metastatic cancer are down-regulated in colonocytes, despite the colonocytes being histologically normal. To further understand the role of the cytoskeleton in generating changes in optical markers of cells, we used pharmacological disruption (using colchicine) of the cytoskeleton. We found that differences in optical markers (between AOM- and control-treated rats) were negated by the disruption, suggesting cytoskeletal involvement in the optical changes. These studies provide significant insights into the micro-architectural alterations in early colon carcinogenesis, and may enable optimization of both bio-photonic and molecular risk stratification techniques to personalize colorectal cancer screening.
PLoS ONE 01/2013; 8(2):e57206. · 4.09 Impact Factor
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ABSTRACT: The process of neoplastic transformation of the colon involves a progression through hyperproliferative epithelium through the aberrant crypt foci→small adenoma→large adenoma→invasive cancer→metastatic disease. These are orchestrated by sequential genetic and epigenetic events which provide the underpinnings of cellular alterations such as early induction in proliferation/suppression of apoptosis, along with the late stage increase in invasiveness. Colorectal cancer (CRC) averages 49-111 mutations per tumor encompassing 10-15 critical signaling pathways[1]. Accumulating such a high number of mutations requires a fertile mutational field, which is the hallmark of colon carcinogenesis.While genetic susceptibility to colorectal cancer is well-known, at least half of the risk is believed to be due to exogeneous factors (e.g., obesity, diet, exercise). Understanding these risk factors represents a promising mode of tailoring screening modality and intensity. However, previous attempts using these factors (i.e., NCI risk calculator) have only been modestly successful with an area under receiver operating characteristics (ROC) curve (AUC) of just 0.61. One of the most important concepts is that risk is the interaction between these genetic and environmental components and is driven by the variety of polymorphisms. Thus, predicting risk is difficult given the complexity. On the other hand, the colonic mucosa represents the end product of the complex interplay between these multiple factors. The power of field carcinogenesis is that it reflects this interplay between genetics and environment.
Journal of Cancer. 01/2013; 4(3):251-61.
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Luisa A Marcelino,
Mark W Westneat,
Valentina Stoyneva,
Jillian Henss,
Jeremy D Rogers,
Andrew Radosevich,
Vladimir Turzhitsky,
Margaret Siple,
Andrew Fang,
Timothy D Swain,
Jennifer Fung, Vadim Backman
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ABSTRACT: Calcium carbonate skeletons of scleractinian corals amplify light availability to their algal symbionts by diffuse scattering, optimizing photosynthetic energy acquisition. However, the mechanism of scattering and its role in coral evolution and dissolution of algal symbioses during "bleaching" events are largely unknown. Here we show that differences in skeletal fractal architecture at nano/micro-lengthscales within 96 coral taxa result in an 8-fold variation in light-scattering and considerably alter the algal light environment. We identified a continuum of properties that fall between two extremes: (1) corals with low skeletal fractality that are efficient at transporting and redistributing light throughout the colony with low scatter but are at higher risk of bleaching and (2) corals with high skeletal fractality that are inefficient at transporting and redistributing light with high scatter and are at lower risk of bleaching. While levels of excess light derived from the coral skeleton is similar in both groups, the low-scatter corals have a higher rate of light-amplification increase when symbiont concentration is reduced during bleaching, thus creating a positive feedback-loop between symbiont concentration and light-amplification that exposes the remaining symbionts to increasingly higher light intensities. By placing our findings in an evolutionary framework, in conjunction with a novel empirical index of coral bleaching susceptibility, we find significant correlations between bleaching susceptibility and light-scattering despite rich homoplasy in both characters; suggesting that the cost of enhancing light-amplification to the algae is revealed in decreased resilience of the partnership to stress.
PLoS ONE 01/2013; 8(4):e61492. · 4.09 Impact Factor
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ABSTRACT: Normal cell function is dependent on the proper maintenance of chromatin structure. Regulation of chromatin structure is controlled by histone modifications that directly influence chromatin architecture and genome function. Specifically, the histone deacetylase (HDAC) family of proteins modulate chromatin compaction and are commonly dysregulated in many tumors, including colorectal cancer (CRC). However, the role of HDAC proteins in early colorectal carcinogenesis has not been previously reported. We found HDAC1, HDAC2, HDAC3, HDAC5, and HDAC7 all to be up-regulated in the field of human CRC. Furthermore, we observed that HDAC2 up-regulation is one of the earliest events in CRC carcinogenesis and observed this in human field carcinogenesis, the azoxymethane-treated rat model, and in more aggressive colon cancer cell lines. The universality of HDAC2 up-regulation suggests that HDAC2 up-regulation is a novel and important early event in CRC, which may serve as a biomarker. HDAC inhibitors (HDACIs) interfere with tumorigenic HDAC activity; however, the precise mechanisms involved in this process remain to be elucidated. We confirmed that HDAC inhibition by valproic acid (VPA) targeted the more aggressive cell line. Using nuclease digestion assays and transmission electron microscopy imaging, we observed that VPA treatment induced greater changes in chromatin structure in the more aggressive cell line. Furthermore, we used the novel imaging technique partial wave spectroscopy (PWS) to quantify nanoscale alterations in chromatin. We noted that the PWS results are consistent with the biological assays, indicating a greater effect of VPA treatment in the more aggressive cell type. Together, these results demonstrate the importance of HDAC activity in early carcinogenic events and the unique role of higher-order chromatin structure in determining cell tumorigenicity.
PLoS ONE 01/2013; 8(5):e64600. · 4.09 Impact Factor
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ABSTRACT: Which range of structures contributes to light scattering in a continuous random media, such as biological tissue? In this Letter, we present a model to study the structural length-scale sensitivity of scattering in continuous random media under the Born approximation. The scattering coefficient μ<sub>s</sub>, backscattering coefficient μ<sub>b</sub>, anisotropy factor g, and reduced scattering coefficient μs* as well as the shape of the spatial reflectance profile are calculated under this model. For media with a biologically relevant Henyey-Greenstein phase function with g∼0.93 at wavelength λ=633 nm, we report that μs* is sensitive to structural length-scales from 46.9 nm to 2.07 μm (i.e., λ/13 to 3λ), μ<sub>b</sub> is sensitive from 26.7 to 320 nm (i.e., λ/24 to λ/2), and the spatial reflectance profile is sensitive from 30.8 nm to 2.71 μm (i.e., λ/21 to 4λ).
Optics Letters 12/2012; 37(24):5220-2. · 3.40 Impact Factor
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ABSTRACT: Several biomedical applications, such as detection of dysplasia, require selective interrogation of superficial tissue structures less than a few hundred micrometers thick. Techniques and methods have been developed to limit the penetration depth of light in tissue, including the design of systems such as fiber-optic probes that have overlapping illumination and collection areas on the tissue surface. For such geometries, the diffusion approximation to the light-transport equation typically does not apply, and as a result there is no general model to extract tissue optical properties from reflectance measurements. In the current study, we employ Monte Carlo (MC) simulations to develop simple and compact analytical models for the light reflectance from these overlapping geometries. These models incorporate the size of the illumination and collection areas, the collection angle, the polarization of the incident light, and the optical properties of the sample. Moreover, these MC simulations use the Whittle-Matérn model to describe scattering from spatially continuous refractive index media such as tissue, which is more general than models based on the conventionally used Henyey-Greenstein model. We validated these models on tissue-simulating phantoms. The models developed herein will facilitate the extraction of optical properties and aid in the design of optical systems employing overlapping illumination and collection areas, including fiber-optic probes for in vivo tissue diagnosis.
Applied Optics 11/2012; 51(33):8013-21. · 1.41 Impact Factor
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ABSTRACT: We here develop a method to measure and image the full optical scattering properties by inverse spectroscopic optical coherence tomography (ISOCT). Tissue is modelled as a medium with continuous refractive index (RI) fluctuation and such a fluctuation is described by the RI correlation functions. Under the first-order Born approximation, the forward model is established for ISOCT. By measuring optical quantities of tissue including the scattering power of the OCT spectrum, the reflection albedo α defined as the ratio of scattering coefficient μ<sub>s</sub>, and the backscattering coefficient μ<sub>b</sub>, we are able to inversely deduce the RI correlation function and image the full set of optical scattering properties.
Optics Letters 11/2012; 37(21):4443-5. · 3.40 Impact Factor
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ABSTRACT: We present an open source electric field tracking Monte Carlo program to model backscattering in biological media containing birefringence, with computation of the coherent backscattering phenomenon as an example. These simulations enable the modeling of tissue scattering as a statistically homogeneous continuous random media under the Whittle-Matérn model, which includes the Henyey-Greenstein phase function as a special case, or as a composition of discrete spherical scatterers under Mie theory. The calculation of the amplitude scattering matrix for the above two cases as well as the implementation of birefringence using the Jones N-matrix formalism is presented. For ease of operator use and data processing, our simulation incorporates a graphical user interface written in MATLAB to interact with the underlying C code. Additionally, an increase in computational speed is achieved through implementation of message passing interface and the semi-analytical approach. Finally, we provide demonstrations of the results of our simulation for purely scattering media and scattering media containing linear birefringence.
Journal of Biomedical Optics 11/2012; 17(11):115001. · 3.16 Impact Factor
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Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 10/2012; · 5.64 Impact Factor
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ABSTRACT: Low-coherence enhanced backscattering (LEBS) spectroscopy is an angular resolved backscattering technique that is sensitive to sub-diffusion light transport length scales in which information about scattering phase function is preserved. Our group has shown the ability to measure the spatial backscattering impulse response function along with depth-selective optical properties in tissue ex-vivo using LEBS. Here we report the design and implementation of a lens-free fiber optic LEBS probe capable of providing depth-limited measurements of the reduced scattering coefficient in-vivo. Experimental measurements combined with Monte Carlo simulation of scattering phantoms consisting of polystyrene microspheres in water are used to validate the performance of the probe. Additionally, depth-limited capabilities are demonstrated using Monte Carlo modeling and experimental measurements from a two-layered phantom.
Optics Express 08/2012; 20(18):19643-57. · 3.59 Impact Factor
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ABSTRACT: We developed a structured interference optical coherence tomography (SIOCT) to enhance the lateral resolution beyond the diffraction limit. A sinusoidal pattern is created on the interferometric beam with the reference intensity temporally modulated. In the Fourier domain, the high spatial frequencies are shifted into the detectable range, which enhances the lateral resolution beyond the diffraction limit by a factor of 2. The lateral resolution of SIOCT was characterized in our study as ~5.5 μm, surpassing the diffraction limit ~9.6 μm as in conventional Fourier-domain optical coherence tomography. SIOCT was demonstrated on phantoms and ex vivo adipose tissues.
Optics Letters 08/2012; 37(15):3048-50. · 3.40 Impact Factor
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ABSTRACT: Polarization-gating has been widely used to probe superficial tissue structures, but the penetration depth properties of this method have not been completely elucidated. This study employs a polarization-sensitive Monte Carlo method to characterize the penetration depth statistics of polarization-gating. The analysis demonstrates that the penetration depth depends on both the illumination-collection geometry [illumination-collection area (R) and collection angle (θ(c))] and on the optical properties of the sample, which include the scattering coefficient (μ(s)), absorption coefficient (μ(a)), anisotropy factor (g), and the type of the phase function. We develop a mathematical expression relating the average penetration depth to the illumination-collection beam properties and optical properties of the medium. Finally, we quantify the sensitivity of the average penetration depth to changes in optical properties for different geometries of illumination and collection. The penetration depth model derived in this study can be applied to optimizing application-specific fiber-optic probes to target a sampling depth of interest with minimal sensitivity to the optical properties of the sample.
Applied Optics 07/2012; 51(20):4627-37. · 1.41 Impact Factor
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Journal of Biomedical Optics 05/2012; 17(5):059801. · 3.16 Impact Factor
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Dhwanil Damania,
Hemant K Roy,
Hariharan Subramanian,
David S Weinberg,
Douglas K Rex,
Michael J Goldberg,
Joseph Muldoon,
Lusik Cherkezyan,
Yuanjia Zhu,
Laura K Bianchi,
Dhiren Shah,
Prabhakar Pradhan,
Monica Borkar,
Henry Lynch, Vadim Backman
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ABSTRACT: Developing a minimally invasive and cost-effective prescreening strategy for colon cancer is critical because of the impossibility of conducting colonoscopy on the entire at-risk population. The concept of field carcinogenesis, in which normal-appearing tissue away from a tumor has molecular and, consequently, nano-architectural abnormalities, offers one attractive approach to identify high-risk patients. In this study, we investigated whether the novel imaging technique partial wave spectroscopic (PWS) microscopy could risk-stratify patients harboring precancerous lesions of the colon, using an optically measured biomarker (L(d)) obtained from microscopically normal but nanoscopically altered cells. Rectal epithelial cells were examined from 146 patients, including 72 control patients, 14 patients with diminutive adenomas, 20 patients with nondiminutive/nonadvanced adenomas, 15 patients with advanced adenomas/high-grade dysplasia, 12 patients with genetic mutation leading to Lynch syndrome, and 13 patients with cancer. We found that the L(d) obtained from rectal colonocytes was well correlated with colon tumorigenicity in our patient cohort and in an independent validation set of 39 additional patients. Therefore, our findings suggest that PWS-measured L(d) is an accurate marker of field carcinogenesis. This approach provides a potential prescreening strategy for risk stratification before colonoscopy.
Cancer Research 04/2012; 72(11):2720-7. · 7.86 Impact Factor
