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Validity of the semi-infinite tumor model in diffuse reflectance spectroscopy for epithelial cancer diagnosis: A Monte Carlo study
Optics Express
Abstract
The accurate understanding of optical properties of human tissues plays an important role in the optical diagnosis of early epithelial cancer. Many inverse models used to determine the optical properties of a tumor have assumed that the tumor was semi-infinite, which infers infinite width and length but finite thickness. However, this simplified assumption could lead to large errors for small tumor, especially at the early stages. We used a modified Monte Carlo code, which is able to simulate light transport in a layered tissue model with buried tumor-like targets, to investigate the validity of the semi-infinite tumor assumption in two common epithelial tissue models: a squamous cell carcinoma (SCC) tissue model and a basal cell carcinoma (BCC) tissue model. The SCC tissue model consisted of three layers, i.e. the top epithelium, the middle tumor and the bottom stroma. The BCC tissue model also consisted of three layers, i.e. the top epidermis, the middle tumor and the bottom dermis. Diffuse reflectance was simulated for two common fiber-optic probes. In one probe, both source and detector fibers were perpendicular to the tissue surface; while in the other, both fibers were tilted at 45 degrees relative to the normal axis of the tissue surface. It was demonstrated that the validity of the semi-infinite tumor model depends on both the fiber-optic probe configuration and the tumor dimensions. Two look-up tables, which relate the validity of the semi-infinite tumor model to the tumor width in terms of the source-detector separation, were derived to guide the selection of appropriate tumor models and fiber optic probe configuration for the optical diagnosis of early epithelial cancers.
... Next, we quantify sampling depth for the shallow and deep SDSs of the sDRS modality and validate results using the same calibration and validation phantoms 59 . Following this, we present a simple phantom study simulating the physical layered progression from healthy tissue to severe dysplasia to show how reflectance changes with an optically scattering heterogeneity buried at various depths 1,2,4 . Finally, the LUT-based inverse model was demonstrated on in vivo human oral mucosa from thirteen healthy volunteers in a laboratory setting to determine volume-averaged scattering exponent, hemoglobin concentration, oxygen saturation, and sampling depth. ...
... Deionized water, polystyrene microspheres and diluted bovine hemoglobin were gently mixed inside 7 mL scintillation vials. This yielded μ s ′ values from 5-26 cm −1 and μ a values from 0-10 cm -1 to validate 100% of the reflectance LUTs. Figure 2 shows the μ s ′ and μ a for the calibration phantoms (C.P. 1-12) and validation phantoms (V.P. [1][2][3][4][5][6][7][8][9]. ...
... Semi-infinite phantom model of dysplastic progression. Once optical property extraction and sampling depth were validated, we tested the capabilities of the sDRS modality of the hybrid fiber-bundle in a dysplasia-mimicking phantom model 1 . Figure 4a-c shows a simplified representation of dysplastic progression starting at the basement membrane and proliferating upwards into surrounding healthy tissue 2,3 . ...
Intraepithelial dysplasia of the oral mucosa typically originates in the proliferative cell layer at the basement membrane and extends to the upper epithelial layers as the disease progresses. Detection of malignancies typically occurs upon visual inspection by non-specialists at a late-stage. In this manuscript, we validate a quantitative hybrid imaging and spectroscopy microendoscope to monitor dysplastic progression within the oral cavity microenvironment in a phantom and pre-clinical study. We use an empirical model to quantify optical properties and sampling depth from sub-diffuse reflectance spectra (450–750 nm) at two source-detector separations (374 and 730 μm). Average errors in recovering reduced scattering (5–26 cm−1) and absorption coefficients (0–10 cm−1) in hemoglobin-based phantoms were approximately 2% and 6%, respectively. Next, a 300 μm-thick phantom tumor model was used to validate the probe’s ability to monitor progression of a proliferating optical heterogeneity. Finally, the technique was demonstrated on 13 healthy volunteers and volume-averaged optical coefficients, scattering exponent, hemoglobin concentration, oxygen saturation, and sampling depth are presented alongside a high-resolution microendoscopy image of oral mucosa from one volunteer. This multimodal microendoscopy approach encompasses both structural and spectroscopic reporters of perfusion within the tissue microenvironment and can potentially be used to monitor tumor response to therapy.
... Within the non-keratinized squamous epithelia, dysplasia typically arises at the basement membrane between the epithelium and underlying connective tissue [1][2][3][4]. In this situation, severity of dysplasia is typically characterized based on how far the dysplastic tissue has spread from the basement membrane towards the apical epithelial surface. ...
... For example, early-stage dysplasia confined at the basement membrane may be considered mild, whereas later-stage dysplasia that has spread to the epithelial surface may be considered severe or even carcinoma in situ. Thus, dysplasia can occur at various layers within the tissue geometry at various thicknesses [1][2][3][4]. ...
In the non-keratinized epithelia, dysplasia typically arises near the basement membrane and proliferates into the upper epithelial layers over time. We present a non-invasive, multimodal technique combining high-resolution fluorescence imaging and broadband sub-diffuse reflectance spectroscopy (sDRS) to monitor health at various tissue layers. This manuscript focuses on characterization of the sDRS modality, which contains two source-detector separations (SDSs) of 374 μm and 730 μm, so that it can be used to extract in vivo optical parameters from human oral mucosa at two tissue thicknesses. First, we present empirical lookup tables (LUTs) describing the relationship between reduced scattering (μ s ′) and absorption coefficients (μ a) and absolute reflectance. LUTS were shown to extract μ s ′ and μ a with accuracies of approximately 4% and 8%, respectively. We then present LUTs describing the relationship between μ s ′, μ a and sampling depth. Sampling depths range between 210–480 and 260–620 μm for the 374 and 730 μm SDSs, respectively. We then demonstrate the ability to extract in vivo μ s ′, μ a , hemoglobin concentration, bulk tissue oxygen saturation, scattering exponent, and sampling depth from the inner lip of thirteen healthy volunteers to elucidate the differences in the extracted optical parameters from each SDS (374 and 730 μm) within non-keratinized squamous epithelia.
... The application of PDT in the treatment of cancers and surface carcinomas is still limited due to the difficulties involved in managing the manifold changes that occur during the PDT process [7,8] the findings from this research can be used as a foundation on which most of the physics related changes (photo-physics) is based. Thus, paving way for the chemist to improve on the nature and control of PS properties, and the biologist to understand and help quantify the accrued effects of the produced singlet oxygen and heat generated during the PDT procedure [9][10][11]. It is thus imperative to state here that the result from the research is not absolute, nor is it independent of other findings. ...
... It would also be interesting to consider 3D tumor models, since the assumption of semi-infinite layers imposed by CudaMCML is a limitation. A study shows that the validity of this assumption depends on the type of tumor simulated (squamous cell carcinoma in epithelium or a basal cell carcinoma in upper dermis), the angular incidence of the exciting fiber, the height of the tumor and its width relative to the SD distance at which the signal is acquired [Zhu 2011]. ...
In the context of cutaneous carcinoma, optical biopsy offers a in-vivo non-destructive alternative to conventional biopsy to inform the dermatologist of the state of health of the deep tissue during cancer resection. The latter is indeed at the origin of morphological and physiological modifications of the skin, which explains why the optical measurements resulting from the light/tissue interactions are sensitive to it. The work presented in this manuscript exploits the data obtained with the optical biopsy device extit{SpectroLive} on about a hundred patients just before cancer resection by the clinician. In contact with the skin, this spectroscopic device acquires diffuse reflectance (white broadband excitation) and autofluorescence (monochromatic emission to excite endogenous fluorophores in the skin) spatially resolved signals, extit{i.e.}, for several separation distances between the light emitting fiber and the collecting fibers at the periphery. This spatial resolution is of particular interest for the skin, since the different distances introduced allow the collection of photons traveling through the different layers in depth (epidermis, dermis and hypodermis) of the organ. The main part of the work presented here concerns the estimation of the optical properties of the skin by solving the inverse problem from these clinical acquisitions. This consists first in establishing a photon transport simulation faithful to the characteristics (geometrical and spectral) of the real device before building a multilayer model of the skin in which the optical parameters (e.g. absorption and scattering coefficients, the anisotropy factor) and geometrical parameters e.g. layer thickness) can be estimated by an optimization process aiming at minimizing the differences between the spectra generated by the simulation and the ``target'' spectra obtained in clinic. The main contributions developed in this manuscript are first the development and the full exploitation of the simulation, with in particular a study whose purpose is to characterize the penetration of the photons detected at the various source/detector separations, and this for various skin models in order to represent the inter- and intra-individual differences. The knowledge acquired with this study of probed depths is then used in the second major contribution, aiming at adapting the process of estimating optical properties from clinical spectra (inverse problem) to the skin. Finally, the last contribution, more metrological, is the development of an optical bench with double integrating spheres allowing to obtain these same optical properties for a sample ex-vivo, and thus to allow the comparison of the estimates resulting from the two modalities.
... It would also be interesting to consider 3D tumor models, since the assumption of semiinfinite layers imposed by CudaMCML is a limitation. A study shows that the validity of this assumption depends on the type of tumor simulated (squamous cell carcinoma in epithelium or a basal cell carcinoma in upper dermis), the angular incidence of the exciting fiber, the height of the tumor and its width relative to the SD distance at which the signal is acquired [65]. ...
In the context of cutaneous carcinoma diagnosis based on in vivo optical biopsy, Diffuse Reflectance (DR) spectra, acquired using a Spatially Resolved (SR) sensor configuration, can be analyzed to distinguish healthy from pathological tissues. The present contribution aims at studying the depth distribution of SR-DR-detected photons in skin from the perspective of analyzing how these photons contribute to acquired spectra carrying local physiological and morphological information. Simulations based on modified Cuda Monte Carlo Modeling of Light transport were performed on a five-layer human skin optical model with epidermal thickness, phototype and dermal blood content as variable parameters using (i) wavelength-resolved scattering and absorption properties and (ii) the geometrical configuration of a multi-optical fiber probe implemented on an SR-DR spectroscopic device currently used in clinics. Through histograms of the maximum probed depth and their exploitation, we provide numerical evidence linking the characteristic penetration depth of the detected photons to their wavelengths and four source–sensor distances, which made it possible to propose a decomposition of the DR signals related to skin layer contributions.
... The most common way of simulating a random scattering system is to use a model based on Monte-Carlo method [16][17][18][19], which is considered to be a 'gold standard' [20] when simulating light transport in a turbid medium; in practice it is often computationally fast as well as accurate when compared to other numerical methods. In a typical Monte-Carlo simulation [16,21], the propagation of light is modelled as propagation of photon packets, with the step size s i between each interaction site, determined as ...
Study of scattered light has emerged as an important and practical method of analysing a turbid medium in a fast and non-invasive manner. From light scattering measurements, the scattering parameters of the turbid medium can be estimated, which in turn depend on the intrinsic properties of the scatterers. Measurements of multiple physical quantities such as transmitted light, reflected light and scattered light at different angles lead to a better estimation of the scattering parameters. Using the scattering theory and simulations such as Monte-Carlo technique, in conjunction with experiments, leads to substantial reduction in the number of measurements required, and help in optimizing efficient and compact devices for practical use. There is also scope for studies on mixtures of turbid media, and the effect of various changes in the ambience, in specific applications. In this paper, we first review the basics of light scattering from turbid media, and briefly discuss the methodologies to simulate and characterize a turbid medium. We then detail some of our recent work on estimation of the scattering parameters of a turbid medium, including the use of fiber-optic probes as turbidity sensors, with potential applications in remote sensing and telemetry.
... We observed that the TC R was always increased with SD for the small or middle tumor models (>5 mm). For these small or middle tumors models, the tumor diameter was larger than the SD values and the tumor can be treated as a semi-infinite layer for diffuse reflectance spectroscopy according to our former study [28]. In the semi-infinite tumor models, the ratio of reflectance signals from tumor region to that from non-tumor would be always increased with SD thereby the TC R was always increased with SD as shown in Fig. 9(a). ...
In most biomedical optical spectroscopy platforms, a fiber-probe consisting of single or multiple illumination and collection fibers was commonly used for the delivery of illuminating light and the collection of emitted light. Typically, the signals from all collection fibers were combined and then sampled to characterize tissue samples. Such simple averaged optical measurements may induce significant errors for in vivo tumor characterization, especially in longitudinal studies where the tumor size and location vary with tumor stages. In this study, we utilized the Monte Carlo technique to optimize the fiber-probe geometries of a spectroscopy platform to enable tumor-sensitive diffuse reflectance and fluorescence measurements on murine subcutaneous tissues with growing solid tumors that have different sizes and depths. Our data showed that depth-sensitive techniques offer improved sensitivity in tumor detection compared to the simple averaged approach in both reflectance and fluorescence measurements. Through the numerical studies, we optimized the source-detector distances, fiber diameters, and numerical apertures for sensitive measurement of small solid tumors with varying size and depth buried in murine subcutaneous tissues. Our study will advance the design of a fiber-probe in an optical spectroscopy system that can be used for longitudinal tumor metabolism and vasculature monitoring.
... Monte Carlo simulations of photon propagation offer a flexible and rigorous approach to solve the problem of light propagation in turbid media with complex structure [8], [9]. The Monte Carlo method is able to solve radiative transport equation (RTE) with any desired accuracy [4], so that, it is frequently used as a reference to validate other less rigorous methods such as the diffuse approximation. ...
... A two-layered sample was made by stacking one layer with R6G on top of the other with the fluorescence microparticles. The transport mean free path (l t = 1/µ s ') of the top layer was around 3.3 mm with a thickness of 110 ± 10 µm, to mimic the epithelium in epithelial tissue [32]. The transport mean free path of the bottom layer was around 10 mm with a thickness from 110 ± 10 µm to serve as the superficial region of the stroma. ...
Depth sensitive optical spectroscopy preferentially detects optical spectra from different depths in layered samples, which plays a crucial role in many applications such as the optical diagnosis of epithelial precancer and cancer. In depth sensitive optical measurements, multiple light scattering in tissues significantly degrades the depth sensitivity to a subsurface target layer. To address this issue, feedback based wavefront shaping led by guide stars can be used to refocus light to increase the depth sensitivity to a target layer. However, the lack of intrinsic guide stars in tissues or tissue-like samples often leads to poor enhancement in depth sensitive Raman/fluorescence measurements (~20% in the past literature) from the target layer due to the contribution from the overlaying non-target layer. In this study, we demonstrate that spatial filtering and spectral filtering can significantly improve the performance of depth sensitive fluorescence spectroscopy assisted by feedback based wavefront shaping in tissue-like scattering phantoms. The two filtering techniques work by effectively increasing the relative contribution from the target layer to the feedback signal during wavefront optimization through spatially and spectrally rejecting off-target fluorescence light, which is essentially similar to the role of time or coherence gating. When the filtering techniques are applied, a maximum of three-fold enhancement in fluorescence contribution from the target layer is observed, which is in contrast to nearly no enhancement in case of no filtering. This significant enhancement has not been reported previously for depth sensitive optical spectroscopy in the area of feedback based wavefront shaping. Therefore, our work represents a new advance towards the application of wavefront shaping in depth resolved optical spectroscopy for the characterization of layered structures such as epithelial tissues or drug tablets, in which the creation of an external guide star is challenging or not allowed.
... Although g f is wavelength-dependent and it can vary between −1 to 1 (-1 corresponding to total backscattering, 0 to isotropic (Rayleigh) scattering and 1 to total forward scattering), healthy tissue measurements classify g f in the range of ∼0.7 to ∼0.9 [8,48], with variations in g f values inducing fluctuations in fluence rate [49]. In case of cancerous tissue higher values of g f , up to 1, have been reported [50,51]. In the present study, for our RIF tumor we adopted a value of g f = 0.95 and as a result μ s value was 269.2 cm −1 . ...
Background:
In photodynamic therapy (PDT) oxygen plays vital role in killing tumor cells and therefore its dosimetry is being thoroughly studied.
Methods:
Light distribution into tissue is modelled for radiation-induced fibrosarcoma (RIF) and nodular basal cell carcinoma (nBCC), in order to study the influence of blood flow on singlet oxygen concentration effectively leading to cell death ([1O2]rx) on PDT, within this light distribution. This is achieved through initial oxygen supply rate (g0) and initial molecular oxygen concentration ([3O2]0) calculations. Monte Carlo simulations and mathematical models are used for spatial and temporal distributions of [1O2]rx. Hypoxia conditions are simulated by minimizing [3O2]0 and g0. Furthermore, an optimization algorithm is developed to calculate minimum initial molecular oxygen concentration needed ([3O2]0,min) for constant [1O2]rx, when blood flow changes.
Results:
Our results validate that in initially well-oxygenated scenarios with normal blood flow maximum [1O2]rx values are significantly higher than corresponding values of hypoxic scenarios both for RIF and nBCC models, with maximum oxygen supply rate percentage variations being independent from g0. Moreover, [1O2]rx appears to be more affected by an increase of g0 than of [3O2]0 values. For low blood flow there is a linear relationship between [3O2]0,min and g0, while for better oxygenated areas high blood flow reduces [3O2]0,min needed in exponential manner.
Conclusions:
Blood flow appears to be able to compensate for oxygen consumption. Finally, the developed optimization protocol on oxygen dosimetry offers the suitable combination of [3O2]0,min and g0 to achieve constant [1O2]rx, despite possible blood flow variations.
... Monte Carlo model has been a non-experimental standard for other light propagation models [11][12][13][14]. Monte Carlo method can be also applied to the research of simulations for theoretical valida- tions [15,16]. ...
... MC simulation has been widely employed to simulate the light distribution in turbid media [43][44][45][46]. Figure 4 shows that established one-layer LUT and two-layer LUT based on MC simulation, which covers the range of absorption coefficient and scattering coefficient of skin in the range of visible-NIR wavelength. For the one-layer LUT, it can be found that when the absorption coefficient (µ a ) is constant, the absorption intensity of blood model (log 10 (1/R)) decreases with the increase of scattering coefficient (µ s ). ...
Hyperspectral imaging combining with skin optical clearing technique provides a possible way to non-invasively monitor hemodynamics of cutaneous microvessels. In order to estimate microvascular blood oxygen saturation, in this work, a lookup-table-based inverse model was developed to extract the microvascular optical and physiological properties using hyperspectral analysis. This approach showed a higher fitting degree than currently existing hyperspectral analysis methods (i.e. multiple linear regression and non-negative least square fit) in estimating blood oxygen saturation. Hypoxic stimulation experiment showed that calculated results were in accordance with physiological changes, and the relative changes of estimated oxygen saturation indicated this method appeared to be more sensitive to blood oxygen fluctuation. And a simulated blood model was used for verification here, indicating this method also showed a good accuracy in determining oxygen saturation from the simulated spectra.
... Monte Carlo simulation is a golden standard for simulating light transport and distribution in biological tissue (22)(23)(24)(25). In order to obtain the scattering coefficient of skull, the relation between coefficient and collimation transmittance was established by using Monte Carlo simulation. ...
In vivo cortex optical imaging methods for visualization of both structural and functional architecture with high spatial-temporal resolution have shown tremendous advantages in the studies on neurons, glia and microvasculature. To overcome the strong scattering of skull above the cortex, several chronic cranial windows were proposed through craniotomy, but there are some problems. Here, an innovative skull optical clearing solution (SOCS) has been invented to make the skull transparent within 25 min, but SOCS-induced optical clearing efficacy of skull is to be evaluated.
Based on the measurements of divergence of beam spot, collimated transmittance of skull, the efficiency of skull optical clearing has been further evaluated quantitatively by comparing with the Monte Carlo simulation.
The results show that the light beam bandwidth is 5.2±0.3 mm through the initial skull, and reduces to 2.0±0.2 mm trough the treated skull with SOCS; and the calculated scattering coefficient almost decreases to one third after the treatment.
The quantitative evaluation of SOCS-induced optical clearing efficacy of skull provides an important reference for performing transcranial cortical optical imaging or operation based on skull optical clearing technique.
... In the field of light migration modeling, Monte Carlo (MC) methods have been considered a "gold standard" [17] since the 1980s. The most common tissue model employed in Monte Carlo simulations is a multi-layer model with homogeneous optical properties within each layer [18]. ...
... As shown in Table 2, the μa, μs and g of the three layers (dermis, fat and muscle) change with the variation of wavelength, while the variations of epidermis parameters are so small that can be ignored [21]. Additionally, the dispersive effect of human skin was ignored in our simulation, and the refractive index was considered as a parameter which did not vary with wavelength [25,26]. ...
Recharging implantable electronics from the outside of the human body is very important for applications such as implantable biosensors and other implantable electronics. In this paper, a recharging method for implantable biosensors based on a wearable incoherent light source has been proposed and simulated. Firstly, we develop a model of the incoherent light source and a multi-layer model of skin tissue. Secondly, the recharging processes of the proposed method have been simulated and tested experimentally, whereby some important conclusions have been reached. Our results indicate that the proposed method will offer a convenient, safe and low-cost recharging method for implantable biosensors, which should promote the application of implantable electronics.
... Monte Carlo simulations are the golden standard for simulating light transport in tissue and have been widely used to simulate light distribution in turbid media [30][31][32][33]. In order to reduce the simulation time, a GPU acceleration technique was adopted, and considering the size of the source fiber, Wang et al.'s CONV program [34] was used to obtain diffuse reflectance (R(r)). ...
Fiber reflectance spectroscopy is a non-invasive method for diagnosing skin diseases or evaluating aesthetic efficacy, but it is dependent on the inverse model validity. In this work, a lookup-table-based inverse model is developed using two-layered Monte Carlo simulations in order to extract the physiological and optical properties of skin. The melanin volume fraction and blood oxygen parameters are extracted from fiber reflectance spectra of in vivo human skin. The former indicates good coincidence with a commercial skin-melanin probe, and the latter (based on forearm venous occlusion and ischemia, and hot compress experiment) shows that the measurements are in agreement with physiological changes. These results verify the potential of this spectroscopy technique for evaluating the physiological characteristics of human skin.
... Even though g was studied in different homogenous biological media, accuracy of optical parameter extraction and the complexity of the inverse problem solution for inhomogeneous media are still under investigation [14]. A variety of approximation, such as Monte Carlo simulation of the photon behavior, has been extended to two layer diffusion, but it would require high amount of computational power [15]. The analytical model of photon transport in tissue using FEM has been first introduced by Arridge et al. in 1993 [16] to demonstrate the ability of FEM to model the photon density inside an object with photon flux along the geometric boundaries. ...
Modeling behavior of broadband (30-1000 MHz) frequency modulated near infrared photons through a multilayer phantom is of interest to optical bio-imaging research. Photon dynamics in phantom are predicted using three-dimension (3D) finite element numerical simulation and are related to the measured insertion loss and phase for a given human head geometry in this paper based on three layers of phantom each with distinct optical parameter properties. Simulation and experimental results are achieved for single, two, and three layers solid phantoms using COMSOL (COMSOL AB, Tegnérgatan 23, SE-111 40, Stockholm, Sweden) (for FEM) simulation and custom-designed broadband free space optical transmitter (Tx) and receiver (Rx) modules that are developed for photon migration at wavelengths of 680, 795, and 850 nm. Standard error is used to compute error between two-dimension and 3D FE modeling along with experimental results by fitting experimental data to the functional form of afrequency+b. Error results are shown at narrowband and broadband frequency modulation. Confidence in numerical modeling of the photonic behavior using 3D FEM for human head has been established here by comparing the reflection mode's experimental results with the predictions made by COMSOL for known commercial solid brain phantoms. Copyright © 2013 John Wiley & Sons, Ltd.
... Even though the anisotropic factor, g, was studied in different homogenous biological media, 21 the complexity of the inverse problem solving for inhomogeneous media is time consuming, and accuracy of the extracted optical parameters is still under investigation. 9,10,22 Therefore, a variety of approximations, such as modeling the photon behavior through MC simulation, has been reported. 23 The basic premise of MC simulation is that complex interactions of particles and biological matter can be treated as a stochastic process, with simulated random movement samples from probability density functions. ...
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.
In the recent past, optical spectroscopy and imaging methods for biomedical diagnosis and target enhancing have been widely researched. The challenge to improve the performance of these methods is to know the sensitive depth of the backwards detected light well. Former research mainly employed a Monte Carlo method to run simulations to statistically describe the light sensitive depth. An experimental method for investigating the sensitive depth was developed and is presented here. An absorption plate was employed to remove all the light that may have travelled deeper than the plate, leaving only the light which cannot reach the plate. By measuring the received backwards light intensity and the depth between the probe and the plate, the light intensity distribution along the depth dimension can be achieved. The depth with the maximum light intensity was recorded as the sensitive depth. The experimental results showed that the maximum light intensity was nearly the same in a short depth range. It could be deduced that the sensitive depth was a range, rather than a single depth. This sensitive depth range as well as its central depth increased consistently with the increasing source-detection distance. Relationships between sensitive depth and optical properties were also investigated. It also showed that the reduced scattering coefficient affects the central sensitive depth and the range of the sensitive depth more than the absorption coefficient, so they cannot be simply added as reduced distinct coefficients to describe the sensitive depth. This study provides an efficient method for investigation of sensitive depth. It may facilitate the development of spectroscopy and imaging techniques for biomedical diagnosis and underwater imaging.
The scaling Monte Carlo method and Gaussian model are applied to simulate the transportation of light beam with arbitrary waist radius. Much of the time, Monte Carlo simulation is performed for pencil or cone beam where the initial status of the photon is identical. In practical application, incident light is always focused on the sample to form approximate Gauss distribution on the surface. With alteration of focus position in the sample, the initial status of the photon will not be identical any more. Using the hyperboloid method, the initial reflect angle and coordinates are generated statistically according to the size of Gaussian waist and focus depth. Scaling calculation is performed with baseline data from standard Monte Carlo simulation. The scaling method incorporated with the Gaussian model was tested, and proved effective over a range of scattering coefficients from 20% to 180% relative to the value used in baseline simulation. In most cases, percentage error was less than 10%. The increasing of focus depth will result in larger error of scaled radial reflectance in the region close to the optical axis. In addition to evaluating accuracy of scaling the Monte Carlo method, this study has given implications for inverse Monte Carlo with arbitrary parameters of optical system.
A general survey is provided on the capability of Monte Carlo (MC) modeling in tissue optics while paying special attention to the recent progress in the development of methods for speeding up MC simulations. The principles of MC modeling for the simulation of light transport in tissues, which includes the general procedure of tracking an individual photon packet, common light-tissue interactions that can be simulated, frequently used tissue models, common contact/noncontact illumination and detection setups, and the treatment of time-resolved and frequency-domain optical measurements, are briefly described to help interested readers achieve a quick start. Following that, a variety of methods for speeding up MC simulations, which includes scaling methods, perturbation methods, hybrid methods, variance reduction techniques, parallel computation, and special methods for fluorescence simulations, as well as their respective advantages and disadvantages are discussed. Then the applications of MC methods in tissue optics, laser Doppler flowmetry, photodynamic therapy, optical coherence tomography, and diffuse optical tomography are briefly surveyed. Finally, the potential directions for the future development of the MC method in tissue optics are discussed.
Lens based setups have been explored for non-contact diffuse reflectance measurements to reduce the uncertainty due to inconsistent probe-sample pressure in the past years. However, there have been no reports describing the details of Monte Carlo modeling of lens based non-contact setup for depth sensitive diffuse reflectance measurements to the best of our knowledge. In this study, we first presented a flexible Monte Carlo method to model non-contact diffuse reflectance measurements in a lens based setup. Then this method was used to simulate diffuse reflectance measurements from a squamous cell carcinoma (SCC) tissue model in the cone shell, cone and hybrid configurations, in which the cone shell configuration has not been previously proposed in optical spectroscopy. Depth sensitive measurements were achieved by adjusting the following two parameters: (1) the depth of focal point of the imaging lens in the SCC model; and (2) the cone radius in the cone configuration or the ring radius in the cone shell configuration. It was demonstrated that the cone shell and the hybrid configurations in general have better depth sensitivity to the tumor and the stroma than the more commonly used cone configuration for diffuse reflectance measurements in the SCC model.
We present a hybrid method that combines a multilayered scaling method and a perturbation method to speed up the Monte Carlo simulation of diffuse reflectance from a multilayered tissue model with finite-size tumor-like heterogeneities. The proposed method consists of two steps. In the first step, a set of photon trajectory information generated from a baseline Monte Carlo simulation is utilized to scale the exit weight and exit distance of survival photons for the multilayered tissue model. In the second step, another set of photon trajectory information, including the locations of all collision events from the baseline simulation and the scaling result obtained from the first step, is employed by the perturbation Monte Carlo method to estimate diffuse reflectance from the multilayered tissue model with tumor-like heterogeneities. Our method is demonstrated to shorten simulation time by several orders of magnitude. Moreover, this hybrid method works for a larger range of probe configurations and tumor models than the scaling method or the perturbation method alone.
Optical coherence tomography (OCT) is a promising method in the early diagnosis of oral cavity cancer. The objective of the present study is to determine normal values of epithelial thickness in the oral cavity, as no such data are to be found in the literature. In healthy test persons, epithelial thickness of the oral mucosa was determined with the help of OCT separately for each side at nine different locations. Special attention was directed to those sites having the highest incidence for the development of dysplasias and carcinomas. Depending on the location within the oral cavity, the epithelium demonstrated a varying thickness. The highest values were found in the region of the tongue and the cheek, whereas the floor of the mouth showed the thinnest epithelium. Our data serve as reference values for detecting oral malignancy and determining the approximate grade of dysplasia. In this circumstance, a differentiated view of the different regions is important due to the variation in thickness of the epithelium within the normal oral cavity.
The object of this study was to investigate whether laser-induced skin autofluorescence (LIF) and/or light reflectance spectra could provide a useful contrast between basal cell carcinoma (BCC) tissues and the surrounding healthy skin. Unstained human skin samples, excised from humans undergoing biopsy examination, were irradiated with a nitrogen laser (lambda = 337 nm) for excitation of autofluorescence and a tungsten halogen lamp for the reflectance measurements. The ex vivo spectroscopic results were correlated with the histopathology images to distinguish the areas of BCC from those of the surrounding health skin. A simple spectral analysis technique was also applied for better skin diagnosis. In conclusion, it seems that LIF and reflectance spectra could be used to differentiate neoplastic from normal skin tissue using an appropriate classification model analysis.
We present a Monte Carlo model to predict fluorescence spectra of the oral mucosa obtained with a depth-selective fiber optic probe as a function of tissue optical properties. A model sensitivity analysis determines how variations in optical parameters associated with neoplastic development influence the intensity and shape of spectra, and elucidates the biological basis for differences in spectra from normal and premalignant oral sites. Predictions indicate that spectra of oral mucosa collected with a depth-selective probe are affected by variations in epithelial optical properties, and to a lesser extent, by changes in superficial stromal parameters, but not by changes in the optical properties of deeper stroma. The depth selective probe offers enhanced detection of epithelial fluorescence, with 90% of the detected signal originating from the epithelium and superficial stroma. Predicted depth-selective spectra are in good agreement with measured average spectra from normal and dysplastic oral sites. Changes in parameters associated with dysplastic progression lead to a decreased fluorescence intensity and a shift of the spectra to longer emission wavelengths. Decreased fluorescence is due to a drop in detected stromal photons, whereas the shift of spectral shape is attributed to an increased fraction of detected photons arising in the epithelium.
A method is described for measuring optical properties and deriving chromophore concentrations from diffuse reflection measurements at the surface of a turbid medium. The method uses a diffusion approximation model for the diffuse reflectance, in combination with models for the absorption and scattering coefficients. An optical fibre-based set-up, capable of measuring nine spectra from 400 to 1050 nm simultaneously, is used to test the method experimentally. Results of the analyses of phantom and in vivo measurements are presented. These demonstrate that in the wavelength range from 600 to 900 nm, tissue scattering can be described as a simple power dependence of the wavelength and that the tissue absorption can be accurately described by the addition of water, oxy- and deoxyhaemoglobin absorption.
This study assesses one possible cause of inter-patient variation in fluorescence spectroscopy of the cervix: the menstrual cycle. Ten patients with no history of an abnormal Pap smear were seen daily throughout 30 consecutive days of their cycle. Fluorescence excitation-emission matrices were measured from three cervical sites on each patient. Principal component analysis was used to determine which spectral regions varied with the day of the cycle. Classification was performed to assess the influence of menstrual cycle on precancer diagnosis. Variations in the principal component scores and the redox ratio values show that the fluorescence emission spectra at 340-380 nm excitation appear to correlate with the cell metabolism of the cervical epithelium throughout the menstrual cycle; these changes do not affect diagnostic classification. The menstrual cycle affects intra-patient variation but does not appear to cause a significant level of inter-patient variation. It does not need to be controlled for in optical detection strategies based on fluorescence spectroscopy.
Electrical impedance spectroscopy is a technique that has been investigated as a potential method for the diagnosis of epithelial carcinomas. Finite element modelling can provide an insight into the patterns of current flow in normal and pathological epithelium and hence aid in the process of probe design optimization. In order to develop a finite element model of the structure of normal and precancerous cervical squamous epithelium, it was first necessary to obtain the mean values and ranges of a number of morphological tissue parameters. The most important parameters in discriminating normal from neoplastic tissue were identified as being cell size and shape distribution, nuclear-to-cytoplasmic volume ratio and volume of extracellular space. A survey of the literature revealed an absence of reliable quantitative data for these parameters. We therefore present the results of our own basic image analysis on normal and pathological tissue sections, which we hope will be of use to other workers wishing to model cervical squamous epithelium, or other similar tissue structures.
We report coregistration of near-infrared diffuse optical spectroscopy (DOS) and magnetic resonance imaging (MRI) for the study of animal model tumors. A combined broadband steady-state and frequency-domain apparatus was used to determine tissue oxyhemoglobin, deoxyhemoglobin, and water concentration locally in tumors. Simultaneous MRI coregistration provided structural (T2-weighted) and contrast-enhanced images of the tumor that were correlated with the optical measurements. By use of Monte Carlo simulations, the optically sampled volume was superimposed on the MR images, showing precisely which tissue structure was probed optically. DOS and MRI coregistration measurements were performed on seven rats over 20 days and were separated into three tumor tissue classifications: viable, edematous, and necrotic. A ratio of water concentration to total hemoglobin concentration, as measured optically, was performed for each tissue type and showed values for edematous tissue to be greater than viable tissue (1.2 +/- 0.49 M/microM versus 0.48 +/- 0.15 M/microM). Tissue hemoglobin oxygen saturation (StO2) also showed a large variation between tissue types: viable tissue had an optically measured StO2 value of 61 +/- 5%, whereas StO2 determined for necrotic tissue was 43 +/- 6%.
Fluorescence spectroscopy has shown promise for the detection of precancerous changes in vivo. The epithelial and stromal layers of tissue have very different optical properties; the albedo is relatively low in the epithelium and approaches one in the stroma. As precancer develops, the optical properties of the epithelium and stroma are altered in markedly different ways: epithelial scattering and fluorescence increase, and stromal scattering and fluorescence decrease. We present an analytical model of the fluorescence spectrum of a two-layer medium such as epithelial tissue. Our hypothesis is that accounting for the two different tissue layers will provide increased diagnostic information when used to analyze tissue fluorescence spectra measured in vivo. The Beer-Lambert law is used to describe light propagation in the epithelial layer, while light propagation in the highly scattering stromal layer is described with diffusion theory. Predictions of the analytical model are compared to results from Monte Carlo simulations of light propagation under a range of optical properties reported for normal and precancerous epithelial tissue. In all cases, the mean square error between the Monte Carlo simulations and the analytical model are within 15%. Finally, model predictions are compared to fluorescence spectra of normal and precancerous cervical tissue measured in vivo; the lineshape of fluorescence agrees well in both cases, and the decrease in fluorescence intensity from normal to precancerous tissue is correctly predicted to within 5%. Future work will explore the use of this model to extract information about changes in epithelial and stromal optical properties from clinical measurements and the diagnostic value of these parameters.
The diffuse reflectance spectrum of human skin in the visible region (400-800 nm) contains information on the concentrations of chromophores such as melanin and haemoglobin. This information may be extracted by fitting the reflectance spectrum with an optical diffusion based analytical expression applied to a layered skin model. With the use of the analytical expression, it is assumed that light transport is dominated by scattering. For port wine stain (PWS) and highly pigmented human skin, however, this assumption may not be valid resulting in a potentially large error in visual reflectance spectroscopy (VRS). Monte Carlo based techniques can overcome this problem but are currently too computationally intensive to be combined with previously used fitting procedures. The fitting procedure presented herein is based on a library search which enables the use of accurate reflectance spectra based on forward Monte Carlo simulations or diffusion theory. This allows for accurate VRS to characterize chromophore concentrations in PWS and highly pigmented human skin. The method is demonstrated using both simulated and measured reflectance spectra. An additional advantage of the method is that the fitting procedure is very fast.
Reflectance spectroscopy is a promising technology for detection of epithelial precancer. Fiber-optic probes that selectively collect scattered light from both the epithelium and the underlying stroma are likely to improve diagnostic performance of in vivo reflectance spectroscopy by revealing diagnostic features unique to each layer. We present Monte Carlo models with which to evaluate fiber-optic probe geometries with respect to sampling depth and depth resolution. We propose a probe design that utilizes half-ball lens coupled source and detector fibers to isolate epithelial scattering from stromal scattering and hence to resolve spectral information from the two layers. The probe is extremely compact and can provide easy access to different organ sites.
Differences in absorption and/or scattering of cancerous and normal skin have the potential to provide a basis for noninvasive cancer detection. In this study, we have determined and compared the in vitro optical properties of human epidermis, dermis, and subcutaneous fat with those of nonmelanoma skin cancers in the spectral range from 370 to 1600 nm. Fresh specimens of normal and cancerous human skin were obtained from surgeries. The samples were rinsed in saline solution and sectioned. Diffuse reflectance and total transmittance were measured using an integrating sphere spectrophotometer. Absorption and reduced scattering coefficients were calculated from the measured quantities using an inverse Monte Carlo technique. The differences between optical properties of each normal tissue-cancer pair were statistically analyzed. The results indicate that there are significant differences in the scattering of cancerous and healthy tissues in the spectral range from 1050 to 1400 nm. In this spectral region, the scattering of cancerous lesions is consistently lower than that of normal tissues, whereas absorption does not differ significantly, with the exception of nodular basal cell carcinomas (BCC). Nodular BCCs exhibit significantly lower absorption as compared to normal skin. Therefore, the spectral range between 1050 and 1400 nm appears to be optimal for nonmelanoma skin cancer detection.
We explored the use of diffuse reflectance spectroscopy in the ultraviolet-visible (UV-VIS) spectrum for the diagnosis of epithelial precancers and cancers in vivo. A physical model (Monte Carlo inverse model) and an empirical model (principal component analysis, (PCA)) based approach were compared for extracting diagnostic features from diffuse reflectance spectra measured in vivo from the dimethylbenz[alpha]anthracene-treated hamster cheek pouch model of oral carcinogenesis. These diagnostic features were input into a support vector machine algorithm to classify each tissue sample as normal (n=10) or neoplastic (dysplasia to carcinoma, n=10) and cross-validated using a leave one out method. There was a statistically significant decrease in the absorption and reduced scattering coefficient at 460 nm in neoplastic compared to normal tissues, and these two features provided 90% classification accuracy. The first two principal components extracted from PCA provided a classification accuracy of 95%. The first principal component was highly correlated with the wavelength-averaged reduced scattering coefficient. Although both methods show similar classification accuracy, the physical model provides insight into the physiological and structural features that discriminate between normal and neoplastic tissues and does not require a priori, a representative set of spectral data from which to derive the principal components.
We introduce a novel and efficient method to provide solutions to inverse photon migration problems in heterogeneous turbid media. The method extracts derivative information from a single Monte Carlo simulation to permit the rapid determination of rates of change in the detected photon signal with respect to perturbations in background tissue optical properties. We then feed this derivative information to a nonlinear optimization algorithm to determine the optical properties of the tissue heterogeneity under examination. We demonstrate the use of this approach to solve rapidly a two-region inverse problem of photon migration in the transport regime, for which diffusion-approximation-based approaches are not applicable.
Diffuse reflectance spectra were collected from adenomatous colon polyps (cancer precursors) and normal colonic mucosa of patients undergoing colonoscopy. We analyzed the data by using an analytical light diffusion model, which was tested and validated on a physical tissue model composed of polystyrene beads and hemoglobin. Four parameters were obtained: hemoglobin concentration, hemoglobin oxygen saturation, effective scatterer density, and effective scatterer size. Normal and adenomatous tissue sites exhibited differences in hemoglobin concentration and, on average, in effective scatterer size, which were in general agreement with other studies that employ standard methods. These results suggest that diffuse reflectance can be used to obtain tissue information about tissue structure and composition in vivo.
To understand better the optical characteristics and autofluorescence properties of normal and carcinomatous bronchial tissue, we measured the absorption coefficient, scattering coefficient, and anisotropy factor from 400 to 700 nm. We made the measurements by using an integrating sphere with a collimated white-light beam to measure total reflectance and transmittance of samples. The unscattered transmittance of the samples was measured through polarized on-axis light detection. The inverse adding-doubling solution was utilized to solve the equation of radiative transfer and to determine the absorption coefficient and reduced scattering coefficient. The scattering coefficient and anisotropy factor were derived from the unscattered transmittance of the sample and the reduced scattering coefficient. The measured parameters allow us to simulate photon propagation in normal bronchial and tumoral tissue by using Monte Carlo modeling.
A source of error in the Monte Carlo simulation of the fluence rate in turbid media is the inaccurate recording of unscattered absorption events. The form and magnitude of the error have been studied for Gaussian and uniform beam profiles simulated in cylindrical and Cartesian coordinates. In each case the error decreases as the lateral sampling lattice spacing decreases and is less than 2% of the incident peak irradiance when the beam radius is greater than five lattice spacings. To avoid the error, one may calculate analytically the fluence rate caused by unscattered absorption events.
Regional epidermal thickening and hair follicle width measurement by delayed gadolinium contrast magnetic resonance imaging (MRI) may assess the contrast agent gadolinium toxicity on mice skin.
Delayed contrast in vivo MRI was performed in mice. Six mice skin samples were removed and exposed to a gadolinium contrast agent at different times after 2, 4, 6 and 8 h. The relaxation constants of each skin structure were measured. The thickness of the epidermis and hair follicle on follow-up ex vivo delayed-contrast MRI served as an index of gadolinium toxicity on the skin.
In vivo MRI by fast low-angle shot imaging technique showed distinct skin layers. High-resolution gradient echo T1-weighted and multislice multiecho proton density-weighted MRI intensities in the epidermis and hair follicle showed a positive correlation with delayed gadolinium-enhanced MRI hyperintensities (Pearson's correlation coefficient r(2)=0.81, P<0.0001) in the excised mice skin tissues. Delayed contrast-enhanced mice skin MRI after 2-4 h showed epidermis swelling and hair follicle regions with a size measurement accuracy of 65%, a sensitivity of 95%, a specificity of 25%, a positive predictive value of 65% and a negative predictive value of 65%. Areas under the receiver operating characteristic curves by MRI were 0.92-0.94 for hair and epidermis as good discriminators. MRI visualized distinct relaxation constants of the epidermis, sebaceous gland, skin papillary and reticular dermis layers and hair follicle.
Gadolinium contrast-enhanced MRI may visualize the thickening of the epidermis wall and hair follicle as an index of viable mice skin. Gadolinium enhanced the MRI visibility of skin structures. Gadolinium treatment showed skin toxicity as epidermis thickening the first time due to the undesirable use of high concentrations of gadolinium in microimaging.
Using optical interaction coefficients typical of mammalian soft tissues in the red and near infrared regions of the spectrum, calculations of fluence-depth distributions, effective penetration depths and diffuse reflectance from two models of radiative transfer, diffusion theory, and Monte Carlo simulation are compared for a semi-infinite medium. The predictions from diffusion theory are shown to be increasingly inaccurate as the albedo tends to zero and/or the average cosine of scatter tends to unity.
A Monte Carlo computer model has been developed to study the propagation of light in tissues. Light attenuation is assumed to result from absorption and isotropic scattering. The model has been used to predict the distribution of absorbed dose in homogeneous tissues of different absorption/scattering ratios, for illumination both by external light beams and via implanted optical fibers. The photon flux into optical fibers placed in the tissue as detectors has also been investigated. The results are interpreted in relation to the use of visible light irradiation for photo radiation therapy.
A Monte Carlo model of steady-state light transport in multi-layered tissues (MCML) has been coded in ANSI Standard C; therefore, the program can be used on various computers. Dynamic data allocation is used for MCML, hence the number of tissue layers and grid elements of the grid system can be varied by users at run time. The coordinates of the simulated data for each grid element in the radial and angular directions are optimized. Some of the MCML computational results have been verified with those of other theories or other investigators. The program, including the source code, has been in the public domain since 1992.
This study evaluates the potential of near-infrared Raman spectroscopy for in vivo detection of squamous dysplasia, a precursor to cervical cancer. A pilot clinical trial was carried out at three
clinical sites. Raman spectra were measured from one colposcopically normal and one abnormal area of the cervix. These sites were then biopsied and submitted for routine histologic analysis. Twenty-four
evaluable measurements were made in vivo in 13 patients. Cervical tissue Raman spectra contain peaks in the vicinity of 1070, 1180, 1195, 1210, 1245, 1330, 1400, 1454, 1505, 1555, 1656, and 1760
cm-1. The ratio of intensities at 1454 to 1656 cm-1 is greater for squamous dysplasia than all other tissue types, while the ratio of intensities at 1330 to 1454 cm-1 is
lower for samples with squamous dysplasia than all other tissue types. A simple algorithm based on these two intensity ratios separates high-grade squamous dysplasia from all others, misclassifying only
one sample. Spectra measured in vivo resemble those measured in vitro. Cervical epithelial cells may contribute to tissue spectra at 1330 cm-1, a region associated with DNA. In
contrast, epithelial cells probably do not contribute to tissue spectra at 1454 cm-1, a region associated with collagen and phospholipids.
We report the isolation and characterization of a spontaneously immortalized human keratinocyte cell line, NIKS. The cell line is not tumorigenic in athymic nude mice and maintains cell-type-specific requirements for growth in vitro. NIKS cells express steady-state levels of transforming growth factor-alpha, transforming growth factor-beta1, epidermal growth factor receptor, c-myc, and keratin 14 mRNAs comparable with the parental BC-1-Ep keratinocyte strain. BC-1-Ep and NIKS keratinocytes produce similar levels of cornified envelopes and nucleosomal fragmentation in response to loss of substrata attachment. DNA fingerprinting results confirm that the NIKS cells originated from the parental BC-1-Ep keratinocytes. NIKS cells contain 47 chromosomes due to an extra isochromosome of the long arm of chromosome 8, and the near-diploid karyotype appears to be stable with repeated passage. A fully stratified squamous epithelium is formed by the NIKS keratinocytes in organotypic culture. Ultrastructural analysis of both the parental and immortalized keratinocytes reveals abundant desmosomes, hemidesmosomes, and the production of a basal lamina. Our findings with the NIKS cells support the observation that spontaneous immortalization is not linked to alterations in squamous differentiation or the ability to undergo apoptosis. The NIKS human keratinocyte cell line is an important new tool for the study of growth and differentiation in stratified squamous epithelia.
At 380 nm excitation, cervical tissue fluorescence spectra demonstrate characteristic changes with both patient age and the presence of dysplasia. A Monte Carlo model was developed in order to quantitatively examine how intrinsic NADH and collagen fluorescence, in combination with tissue scattering and absorption properties, yield measured tissue spectra.
Excitation-emission matrices were measured for live cervical cells and collagen gel phantoms. Fluorescence microscopy of fresh tissue sections was performed to obtain the location and density of fluorophores as a function of patient age and the presence of dysplasia. A Monte Carlo model was developed which incorporated measurements of fluorophore line shapes and spatial distributions.
Modeled spectra were consistent with clinical measurements and indicate that an increase in NADH fluorescence and decrease in collagen fluorescence create clinically observed differences between normal and dysplastic tissue spectra. Model predictions were most sensitive to patient age and epithelial thickness.
Monte Carlo techniques provide an important means to investigate the combined contributions of multiple fluorophores to measured emission spectra. The approach will prove increasingly valuable as a more sophisticated understanding of in vivo optical properties is developed.
Skin thickness varies considerably between different races and age-groups, between men and women, and between different regions of the body surface. A few authors reported the skin thickness of different regions of the body, but no detailed study have been performed on Asian. We performed 452 biopsies on 28 different regions of the normal skin of Korean men and women. The specimens were stained with hematoxylin-eosin and measured microscopically. The thickness of the skin (epidermis plus dermis) ranged from 521 to 1977 microm; the eyelid, prepuce, and inguinal skin was thinnest (521-626 microm), and the back was thickest (1977 microm). The thickness of the epidermis varied from 31 to 637 microm; skin thickness in the prepuce, eyelid, supraclavicular region, postauricular region, and axilla ranged from 31 to 71 microm; the buttock, dorsum of the hand, and dorsum of the foot were relatively thick (138-189 microm); the palm and sole were thickest (601-637 microm). The thickness dermis varied from 469 to 1942 microm; skin thickness in the eyelid, prepuce, inguinal region, and postauricular region ranged from 469 to 645 microm; the buttock, chest, and anterior neck were relatively thick (1318-1586 microm); the back was thickest (1942 microm). The epidermis accounted for 3.7-16.8% of the entire skin in most regions, except in the palm and sole (40.6-44.6%). Thickness data may be useful in harvesting full- or split-thickness skin grafts.
An angled fiber-optic probe that facilitates depth-sensitive fluorescence measurements was developed for enhancing detection of epithelial precancers. The probe was tested on solid, two-layered phantoms and proved to be effective in selectively detecting fluorescence from different layers. Specifically, a larger illumination angle provides greater sensitivity to fluorescence from the top layer as well as yielding an overall higher fluorescence signal. Monte Carlo simulations of a theoretical model of the phantoms demonstrate that increasing the illumination angle results in an increased excitation photon density and, thus, in increased fluorescence generated in the top layer.
Raman spectroscopy has strong potential for providing noninvasive dermatological diagnosis of skin cancer. In this study, confocal Raman microscopy was applied to the dermatological diagnosis for one of the most common skin cancers, basal cell carcinoma (BCC). BCC tissues were obtained from 10 BCC patients using a routine biopsy and used for confocal Raman measurements. Autofluorescence signals from tissues, which interfere with the Raman signals, were greatly reduced using a confocal slit adjustment. Distinct Raman band differences between normal and BCC tissues for the amide I mode and the PO2- symmetric stretching mode showed that this technique has strong potential for use as a dermatological diagnostic tool without the need for statistical treatment of spectral data. It was also possible to precisely differentiate BCC tissue from surrounding noncancerous tissue using the confocal Raman depth profiling technique. We propose that confocal Raman microscopy provides a novel method for dermatological diagnosis since direct observations of spectral differences between normal and BCC tissues are possible.
Computer simulation is used to facilitate the design of fiber-probe geometries that enable enhanced detection of optical signals arising from specific tissue depths. Obtaining understanding of the relationship between fiber-probe design and tissue interrogation is critical when developing strategies for optical detection of epithelial precancers that originate at known depths from the tissue surface. The accuracy of spectroscopic diagnostics may be enhanced by discretely probing the optical properties of epithelium and underlying stroma, within which the morphological and biochemical features vary as a function of depth. While previous studies have investigated controlling tissue-probing depth for fluorescence-based modalities, in this study we focus on the detection of reflected light scattered by tissue. We investigate how the depth of optical interrogation may be controlled through combinations of collection angles, source-detector separations, and numerical apertures. We find that increasing the obliquity of collection fibers at a given source-detector separation can effectively enhance the detection of superficially scattered signals. Fiber numerical aperture provides additional depth selectivity; however, the perturbations in sampling depth achieved through this means are modest relative to the changes generated by modifying the angle of collection and source-detection separation.
Optimization of device-tissue interface parameters may lead to an improvement in the efficacy of fluorescence spectroscopy for minimally invasive disease detection. Although illumination-collection geometry has been shown to have a strong influence on the spatial origin of detected fluorescence, devices that deliver and/or collect light at oblique incidence are not well understood. Simulations are performed using a Monte Carlo model of light propagation in homogeneous tissue to characterize general trends in the intensity and spatial origin of fluorescence detected by angled geometries. Specifically, the influence of illumination angle, collection angle, and illumination-collection spot separation distance are investigated for low and high attenuation tissue cases. Results indicate that oblique-incidence geometries have the potential to enhance the selective interrogation of superficial or subsurface fluorophores at user-selectable depths up to about 0.5 mm. Detected fluorescence intensity is shown to increase significantly with illumination and collection angle. Improved selectivity and signal intensity over normal-incidence geometries result from the overlap of illumination and collection cones within the tissue. Cases involving highly attenuating tissue produce a moderate reduction in the depth of signal origin. While Monte Carlo modeling indicates that oblique-incidence designs can facilitate depth-selective fluorescence spectroscopy, optimization of device performance will require application-specific consideration of optical and biological parameters.
The goal of the work is to experimentally verify Monte Carlo modeling of fluorescence and diffuse reflectance measurements in turbid, tissue phantom models. In particular, two series of simulations and experiments, in which one optical parameter (absorption or scattering coefficient) is varied while the other is fixed, are carried out to assess the effect of the absorption coefficient (mu(a)) and scattering coefficient (mu(s)) on the fluorescence and diffuse reflectance measured from a turbid medium. Moreover, simulations and experiments are carried out for several fiber optic probe geometries that are designed to sample small tissue volumes. Additionally, a group of conversion expressions are derived to convert the optical properties and fluorescence quantum yield measured from tissue phantoms for use in Monte Carlo simulations. The conversions account for the differences between the definitions of the absorption coefficient and fluorescence quantum yield of fluorophores in a tissue phantom model and those in a Monte Carlo simulation. The results indicate that there is good agreement between the simulated and experimentally measured results in most cases. This dataset can serve as a systematic validation of Monte Carlo modeling of fluorescent light propagation in tissues. The simulations are carried out for a wide range of absorption and scattering coefficients as well as ratios of scattering coefficient to absorption coefficient, and thus would be applicable to tissue optical properties over a wide wavelength range (UV-visible/near infrared). The fiber optic probe geometries that are modeled in this study include those commonly used for measuring fluorescence from tissues in practice.
The Monte Carlo-based inverse model of diffuse reflectance described in part I of this pair of companion papers was applied to the diffuse reflectance spectra of a set of 17 malignant and 24 normal-benign ex vivo human breast tissue samples. This model allows extraction of physically meaningful tissue parameters, which include the concentration of absorbers and the size and density of scatterers present in tissue. It was assumed that intrinsic absorption could be attributed to oxygenated and deoxygenated hemoglobin and beta-carotene, that scattering could be modeled by spheres of a uniform size distribution, and that the refractive indices of the spheres and the surrounding medium are known. The tissue diffuse reflectance spectra were evaluated over a wavelength range of 400-600 nm. The extracted parameters that showed the statistically most significant differences between malignant and nonmalignant breast tissues were hemoglobin saturation and the mean reduced scattering coefficient. Malignant tissues showed decreased hemoglobin saturation and an increased mean reduced scattering coefficient compared with nonmalignant tissues. A support vector machine classification algorithm was then used to classify a sample as malignant or nonmalignant based on these two extracted parameters and produced a cross-validated sensitivity and specificity of 82% and 92%, respectively.
A flexible and fast Monte Carlo-based model of diffuse reflectance has been developed for the extraction of the absorption and scattering properties of turbid media, such as human tissues. This method is valid for a wide range of optical properties and is easily adaptable to existing probe geometries, provided a single phantom calibration measurement is made. A condensed Monte Carlo method was used to speed up the forward simulations. This model was validated by use of two sets of liquid-tissue phantoms containing Nigrosin or hemoglobin as absorbers and polystyrene spheres as scatterers. The phantoms had a wide range of absorption (0-20 cm(-1)) and reduced scattering coefficients (7-33 cm(-1)). Mie theory and a spectrophotometer were used to determine the absorption and reduced scattering coefficients of the phantoms. The diffuse reflectance spectra of the phantoms were measured over a wavelength range of 350-850 nm. It was found that optical properties could be extracted from the experimentally measured diffuse reflectance spectra with an average error of 3% or less for phantoms containing hemoglobin and 12% or less for phantoms containing Nigrosin.
A method for estimating the optical properties of two-layered media (such as squamous epithelial tissue) over a range of wavelengths in the ultraviolet-visible spectrum is proposed and tested with Monte Carlo modeling. The method first used a fiber-optic probe with angled illumination and the collection fibers placed at a small separation (<or=300 microm) to restrict the transport of detected light to the top layer. A Monte Carlo-based inverse model for a homogeneous medium was employed to estimate the top layer optical properties from the measured diffuse reflectance spectrum. Then a flat-tip probe with a large source-detector separation (>or=1000 microm) was used to detect diffuse reflectance preferentially from the bottom layer. A second Monte Carlo-based inverse model for a two-layered medium was applied to estimate the bottom layer optical properties, as well as the top layer thickness, given that the top layer optical properties have been estimated. The results of Monte Carlo validation show that this method works well for an epithelial tissue model with a top layer thickness ranging from 200 to 500 microm. For most thicknesses within this range, the absorption coefficients were estimated to within 15% of the true values, the reduced scattering coefficients were estimated to within 20% and the top layer thicknesses were estimated to within 20%. The application of a variance reduction technique to the Monte Carlo modeling proved to be effective in improving the accuracy with which the optical properties are estimated.
We present Monte Carlo modeling studies to provide a quantitative understanding of contrast observed in spatially resolved reflectance spectra of normal and highly dysplastic cervical tissue. Simulations have been carried out to analyze the sensitivity of spectral measurements to a range of changes in epithelial and stromal optical properties that are reported to occur as dysplasia develops and to predict reflectance spectra of normal and highly dysplastic tissue at six different source-detector separations. Simulation results provide important insights into specific contributions of different optical parameters to the overall spectral response. Predictions from simulations agree well with in vivo measurements from cervical tissue and successfully describe spectral differences observed in reflectance measurements from normal and precancerous tissue sites. Penetration depth statistics of photons detected at the six source-detector separations are also presented to reveal the sampling depth profile of the fiber-optic probe geometry simulated. The modeling studies presented provide a framework to meaningfully interpret optical signals obtained from epithelial tissues and to optimize design of optical sensors for in vivo reflectance measurements for precancer detection. Results from this study can facilitate development of analytical photon propagation models that enable inverse estimation of diagnostically relevant optical parameters from in vivo reflectance measurements.
A scaling Monte Carlo method has been developed to calculate diffuse reflectance from multilayered media with a wide range of optical properties in the ultraviolet-visible wavelength range. This multilayered scaling method employs the photon trajectory information generated from a single baseline Monte Carlo simulation of a homogeneous medium to scale the exit distance and exit weight of photons for a new set of optical properties in the multilayered medium. The scaling method is particularly suited to simulating diffuse reflectance spectra or creating a Monte Carlo database to extract optical properties of layered media, both of which are demonstrated in this paper. Particularly, it was found that the root-mean-square error (RMSE) between scaled diffuse reflectance, for which the anisotropy factor and refractive index in the baseline simulation were, respectively, 0.9 and 1.338, and independently simulated diffuse reflectance was less than or equal to 5% for source-detector separations from 200 to 1500 microm when the anisotropy factor of the top layer in a two-layered epithelial tissue model was varied from 0.8 to 0.99; in contrast, the RMSE was always less than 5% for all separations (from 0 to 1500 microm) when the anisotropy factor of the bottom layer was varied from 0.7 to 0.99. When the refractive index of either layer in the two-layered tissue model was varied from 1.3 to 1.4, the RMSE was less than 10%. The scaling method can reduce computation time by more than 2 orders of magnitude compared with independent Monte Carlo simulations.
The relationship between the depth of a target in a turbid medium and the fluorescence ratio profile measured by use of illumination and collection apertures with variable diameters and the same optical path is shown. The forward problem was studied by Monte Carlo simulations of the propagation of fluorescent light through a theoretical model of a biologically relevant system for a range of aperture diameters. The curve of the fluorescence ratio as a function of the aperture diameter is characterized by a maximum/minimum point whose position shifts linearly with the depth of the target. Furthermore, the position of the maximum/minimum is observed to be insensitive to variations in the fluorescence efficiency and to the optical properties of the target layer or the entire medium.
Monte Carlo (MC) modeling of photon transport in tissues is generally performed using simplified functions that only approximate the angular scattering properties of tissue constituents. However, such approximations may not be sufficient for fully characterizing tissue scatterers such as cells. Finite-difference time-domain (FDTD) modeling provides a flexible approach to compute realistic tissue phase functions that describe probability of scattering at different angles. We describe a computational framework that combines MC and FDTD modeling, and allows random sampling of scattering directions from FDTD phase functions. We carry out simulations to assess the influence of incorporating realistic FDTD phase functions on modeling spectroscopic reflectance signals obtained from normal and precancerous epithelial tissues. Simulations employ various fiber optic probe designs to analyze the sensitivity of different probe geometries to FDTD-generated phase functions. Combined MC/FDTD modeling results indicate that the form of the phase function used is an important factor in determining the reflectance profile of tissues, and detected reflectance intensity can change up to approximately 30% when a realistic FDTD phase function is used instead of an approximating function. The results presented need to be taken into account when developing photon propagation models or implementing inverse algorithms to extract optical properties from measurements.
#150891 -$15.00 USD Received 15
- Mhz
MHz, " Skin Res. Technol. 16(3), 339–353 (2010). #150891 -$15.00 USD Received 15 Jul 2011; revised 21 Aug 2011; accepted 21 Aug 2011; published 25 Aug 2011 (C) 2011 OSA 29 August 2011 / Vol. 19, No. 18 / OPTICS EXPRESS 17804 #150891 -$15.00 USD Received 15 Jul 2011; revised 21 Aug 2011; accepted 21 Aug 2011; published 25 Aug 2011 (C) 2011 OSA 29 August 2011 / Vol. 19, No. 18 / OPTICS EXPRESS 17807 #150891 -$15.00 USD Received 15 Jul 2011; revised 21 Aug 2011; accepted 21 Aug 2011; published 25 Aug 2011 (C) 2011 OSA 29 August 2011 / Vol. 19, No. 18 / OPTICS EXPRESS 17812
Nearinfrared Raman spectroscopy for in vivo detection of cervical precancers
- U Utzinger
- D L Heintzelman
- A Mahadevan-Jansen
- A Malpica
- M Follen
- R Richards-Kortum
U. Utzinger, D. L. Heintzelman, A. Mahadevan-Jansen, A. Malpica, M. Follen, and R. Richards-Kortum, "Nearinfrared Raman spectroscopy for in vivo detection of cervical precancers," Appl. Spectrosc. 55(8), 955-959
(2001).
Validity of the semi-infinite tumor model in tissue optics: a Monte Carlo study
- C Zhu
- Q Liu
C. Zhu and Q. Liu, "Validity of the semi-infinite tumor model in tissue optics: a Monte Carlo study," in 2010
Photonics Global Conference (PGC) (IEEE, 2010), pp. 1-4
- Prestin
- Palmer