Biomedical subjects

E M Sevick-Muraca

Publications and source records attributed to E M Sevick-Muraca.

18 recordsLinked to original sources

PubMed2006

Influence of excitation light rejection on forward model mismatch in optical tomography.

Fluorescence enhanced tomography for molecular imaging requires low background for detection and accurate image reconstruction. In this contribution, we show that excitation light leakage is responsible for elevated background and can be minimized with the use of gradient index (GRIN) lenses when using fibre optics to collect propagated fluorescence light from tissue or other biological media. We show that the model mismatch between frequency-domain photon migration (FDPM) measurements and the diffusion approximation prediction is decreased when GRIN lenses are placed prior to the interference filters to provide efficient excitation light rejection. Furthermore, model mismatch is correlated to the degree of excitation light leakage. This work demonstrates the importance of proper light filtering when designing fluorescence optical imaging and tomography.

Artifacts↗

PubMed2005

Tomographic fluorescence imaging in tissue phantoms: a novel reconstruction algorithm and imaging geometry.

A novel image reconstruction algorithm has been developed and demonstrated for fluorescence-enhanced frequency-domain photon migration (FDPM) tomography from measurements of area illumination with modulated excitation light and area collection of emitted fluorescence light using a gain modulated image-intensified charge-coupled device (ICCD) camera. The image reconstruction problem was formulated as a nonlinear least-squares-type simple bounds constrained optimization problem based upon the penalty/modified barrier function (PMBF) method and the coupled diffusion equations. The simple bounds constraints are included in the objective function of the PMBF method and the gradient-based truncated Newton method with trust region is used to minimize the function for the large-scale problem (39919 unknowns, 2973 measurements). Three-dimensional (3-D) images of fluorescence absorption coefficients were reconstructed using the algorithm from experimental reflectance measurements under conditions of perfect and imperfect distribution of fluorophore within a single target. To our knowledge, this is the first time that targets have been reconstructed in three-dimensions from reflectance measurements with a clinically relevant phantom.

Algorithms↗

PubMed2004

Impact of excipient particle size on measurement of active pharmaceutical ingredient absorbance in mixtures using frequency domain photon migration.

A system of dual-component powder mixtures, varying in excipient particle size and concentration of active pharmaceutical ingredient (API), is analyzed using frequency domain photon migration (FDPM) techniques. The results show that the FDPM-measured absorption coefficient increases linearly with increasing API concentration whereas the isotropic scattering coefficient shows no sensitivity to changes in API concentration. It is further seen that the absorption coefficient of blends, owing to the API, is not only linearly dependent on its concentration, but that this relationship is furthermore related to the excipient particle size. Finally, a comparison between near-infrared absorbance and FDPM-measured isotropic scattering as a function of reciprocal particle size is made to highlight FDPM as a powerful particle sizing tool without need for calibration. Overall, this study presents FDPM as a comprehensive method for detection of API concentration independent of excipient particle size.

Absorption↗

PubMed2004

Fluorescence-enhanced optical imaging of large phantoms using single and simultaneous dual point illumination geometries.

Fluorescence-enhanced optical tomography is typically performed using single point illumination and multiple point collection measurement geometry. Single point illumination is often insufficient to illuminate greater volumes of large phantoms and results in an inadequate fluorescent signal to noise ratio (SNR) for the majority of measurements. In this work, the use of simultaneous multiple point illumination geometry is proposed for acquiring a large number of fluorescent measurements with a sufficiently high SNR. As a feasibility study, dual point excitation sources, which are in-phase, were used in order to acquire surface measurements and perform three-dimensional reconstructions on phantoms of large volume and/or significant penetration depth. Measurements were acquired in the frequency-domain using a modulated intensified CCD imaging system under different experimental conditions of target depth (1.4-2.8 cm deep) with a perfect uptake optical contrast. Three-dimensional reconstructions of the fluorescence absorption from the dual point illumination geometry compare well with the reconstructions from the single point illumination geometry. Targets located up to 2 cm deep were located successfully, establishing the feasibility of reconstructions from simultaneous multiple point excitation sources. With improved excitation light rejection, multiple point illumination geometry may prove useful in reconstructing more challenging domains containing deeply embedded targets. Image quality assessment tools are required to determine the optimal measurement geometry for the largest set off imaging tasks.

Breast↗

PubMed2003

A comparison of exact and approximate adjoint sensitivities in fluorescence tomography.

Many approaches to fluorescence tomography utilize some form of regularized nonlinear least-squares algorithm for data inversion, thus requiring repeated computation of the Jacobian sensitivity matrix relating changes in observable quantities, such as emission fluence, to changes in underlying optical parameters, such as fluorescence absorption. An exact adjoint formulation of these sensitivities comprises three terms, reflecting the individual contributions of 1) sensitivities of diffusion and decay coefficients at the emission wavelength, 2) sensitivities of diffusion and decay coefficients at the excitation wavelength, and 3) sensitivity of the emission source term. Simplifying linearity assumptions are computationally attractive in that they cause the first and second terms to drop out of the formulation. The relative importance of the three terms is thus explored in order to determine the extent to which these approximations introduce error. Computational experiments show that, while the third term of the sensitivity matrix has the largest magnitude, the second term becomes increasingly significant as target fluorophore concentration or volume increases. Image reconstructions from experimental data confirm that neglecting the second term results in overestimation of sensitivities and consequently overestimation of the value and volume of the fluorescent target, whereas contributions of the first term are so low that they are probably not worth the additional computational costs.

Algorithms↗

PubMed2002

Assessment of small-angle and angle-averaged structure factor for monitoring electrostatic colloidal interactions using multiply scattered light.

The isotropic scattering coefficients of 143-nm diameter polystyrene latex suspensions were measured using frequency-domain photon migration (FDPM) at 687 and 828 nm as a function of volume fraction (0.05-0.3) and ionic strength (1.0 to 120 mM NaCl equivalents) in order to derive the angle-integrated structure factor, S(q), and structure factor at zero wave vector, S(0). The effective surface charges of the dispersions were estimated by fitting the measured isotropic scattering coefficients at each wavelength as a function of volume fraction to the solution of the Orstein-Zernike integral equation using the hard sphere Yukawa potential model and mean spherical approximation as a closure relation. The estimates of surface charges were comparable at both wavelengths, but decreased with ionic strength. At 120 mM NaCl equivalents, the values of S(0) obtained from FDPM matched those predicted by the Percus-Yevick model, and decreased with volume fraction, consistent with prediction by the Carnahan-Starling equation.

Journal Article↗

PubMed2001

Three-dimensional Bayesian optical image reconstruction with domain decomposition.

Most current efforts in near-infrared optical tomography are effectively limited to two-dimensional reconstructions due to the computationally intensive nature of full three-dimensional (3-D) data inversion. Previously, we described a new computationally efficient and statistically powerful inversion method APPRIZE (automatic progressive parameter-reducing inverse zonation and estimation). The APPRIZE method computes minimum-variance estimates of parameter values (here, spatially variant absorption due to a fluorescent contrast agent) and covariance, while simultaneously estimating the number of parameters needed as well as the size, shape, and location of the spatial regions that correspond to those parameters. Estimates of measurement and model error are explicitly incorporated into the procedure and implicitly regularize the inversion in a physically based manner. The optimal estimation of parameters is bounds-constrained, precluding infeasible values. In this paper, the APPRIZE method for optical imaging is extended for application to arbitrarily large 3-D domains through the use of domain decomposition. The effect of subdomain size on the performance of the method is examined by assessing the sensitivity for identifying 112 randomly located single-voxel heterogeneities in 58 3-D domains. Also investigated are the effects of unmodeled heterogeneity in background optical properties. The method is tested on simulated frequency-domain photon migration measurements at 100 MHz in order to recover absorption maps owing to fluorescent contrast agent. This study provides a new approach for computationally tractable 3-D optical tomography.

Bayes Theorem↗

PubMed2000

Pharmacokinetics of ICG and HPPH-car for the detection of normal and tumor tissue using fluorescence, near-infrared reflectance imaging: a case study.

We present in vivo fluorescent, near-infrared (NIR), reflectance images of indocyanine green (ICG) and carotene-conjugated 2-devinyl-2-(1-hexyloxyethyl) pyropheophorbide (HPPH-car) to discriminate spontaneous canine adenocarcinoma from normal mammary tissue. Following intravenous administration of 1.0 mg kg-1 ICG or 0.3 mg kg-1 HPPH-car into the canine, a 25 mW, 778 nm or 70 mW, 660 nm laser diode beam, expanded by a diverging lens to approximately 4 cm in diameter, illuminated the surface of the mammary tissue. Successfully propagating to the tissue surface, ICG or HPPH-car fluorescence generated from within the tissue was collected by an image-intensified, charge-coupled device camera fitted with an 830 or 710 nm bandpass interference filter. Upon collecting time-dependent fluorescence images at the tissue surface overlying both normal and diseased tissue volumes, and fitting these images to a pharmacokinetic model describing the uptake (wash-in) and release (wash-out) of fluorescent dye, the pharmacokinetics of fluorescent dye was spatially determined. Mapping the fluorescence intensity owing to ICG indicates that the dye acts as a blood pool or blood persistent agent, for the model parameters show no difference in the ICG uptake rates between normal and diseased tissue regions. The wash-out of ICG was delayed for up to 72 h after intravenous injection in tissue volumes associated with disease, because ICG fluorescence was still detected in the diseased tissue 72 h after injection. In contrast, HPPH-car pharmacokinetics illustrated active uptake into diseased tissues, perhaps owing to the overexpression of LDL receptors associated with the malignant cells. HPPH-car fluorescence was not discernable after 24 h. This work illustrates the ability to monitor the pharmacokinetic delivery of NIR fluorescent dyes within tissue volumes as great as 0.5-1 cm from the tissue surface in order to differentiate normal from diseased tissue volumes on the basis of parameters obtained from the pharmacokinetic models.

Adenocarcinoma↗

PubMed1999

Frequency-domain photon migration measurements for quantitative assessment of powder absorbance: A novel sensor of blend homogeneity.

The measurement and analysis of frequency-domain photon migration (FDPM) measurements of powder absorbance in pharmaceutical powders is described in the context of other optical techniques. FDPM consists of launching intensity-modulated light into a powder and detecting the phase delay and amplitude modulation of the re-emitted light as a function of the modulation frequency. From analysis of the data using the diffusion approximation to the radiative transport equation, the absorption coefficient can be obtained. Absorption coefficient measurements of riboflavin in lactose mixtures are presented at concentrations of 0.1 to 1% (w/w) at near-infrared wavelengths where solution absorption cross sections are difficult to accurately measure using traditional transmission measurements in nonscattering solutions. FDPM measurements in powders enabled determinations of absorption coefficients that increase linearly with concentration (w/w) according to Beer-Lambert relationship. The extension of FDPM for monitoring absorbance of low-dose and ultralow-dose powder blending operations is presented.

Absorption↗

PubMed1999

Imaging of spontaneous canine mammary tumors using fluorescent contrast agents.

We present near-infrared frequency-domain photon migration imaging for the lifetime sensitive detection and localization of exogenous fluorescent contrast agents within tissue-simulating phantoms and actual tissues. We employ intensity-modulated excitation light that is expanded and delivered to the surface of a tissue or tissue-simulating phantom. The intensity-modulated fluorescence generated from within the volume propagates to the surface and is collected using a gain-modulated image-intensified charge-coupled device camera. From the spatial values of modulation amplitude and phase of the detected fluorescent light, micromolar volumes of diethylthiatricarbocyanine iodide (tau = 1.17 ns) and indocyanine green (ICG) (tau = 0.58 ns) embedded 1.0 cm deep in a tissue phantom are localized and discriminated on the basis of their lifetime differences. To demonstrate the utility of frequency-domain fluorescent measurements for imaging disease, we image the fluorescence emitted from the surface of in vivo and ex vivo canine mammary gland tissues containing lesions with preferential uptake of ICG. Pathology confirms the ability to detect spontaneous mammary tumors and regional lymph nodes amidst normal mammary tissue and fat as deep as 1.5 cm from the tissue surface.

Animals↗

PubMed1998

Fluorescence lifetime spectroscopic imaging with measurements of photon migration.

Frequency-domain measurements of photon migration are coupled with a model of fluorescence generation and propagation in order to develop a method for reconstructing maps of fluorescent properties within interior tissue volumes from exterior measurements at the air-tissue interface. Simulation results confirm the feasibility of optical imaging through the use of exogenously administered contrast agents on the basis of fluorophore decay kinetics and yield. Experimental measurements using single-pixel and multipixel devices illustrate that the contrast owing to exogenous fluorescence exceeds that owing to absorption or scattering caused by endogenous chromophores or tissue structure and owing to absorption caused by exogenous contrast agents.

Diagnostic Imaging↗

PubMed1997

Fluorescence and absorption contrast mechanisms for biomedical optical imaging using frequency-domain techniques.

The ability to optically image or detect diseased tissue volumes located deep within tissues depends upon the degree of contrast provided by differences in local optical properties. In this report, we show that the exogenous contrast offered by fluorescent compounds is superior to that provided by nonfluorescing, light-absorbing compounds when time-dependent measurements are employed. In addition, we show that the induced contrast is not only moderated by the preferential uptake of fluorescent agents into diseased tissue volumes of interest but also by the fluorescent optical properties and the fluorescence dynamics in the specific tissue volume. Using tissue phantom studies, we demonstrated experimentally that near-infrared-absorbing and fluorescent dyes such as indocyanine green can provide detection of diseased tissue volumes from fluorescence measurements made at the periphery of tissue when there is perfect, 100-fold and 10-fold partitioning in diseased tissues over that in surrounding normal tissues. Experimental results of common laser dyes show the contrast is also mediated by the quantum yield and lifetime parameters that may be dependent upon the local tissue environment.

Diagnosis↗

PubMed1995

Fluorescence lifetime-based sensing in tissues: a computational study.

We have numerically solved the photon diffusion equation to predict the distribution of light in a tissue model system with a uniform concentration of fluorophore. Our results show that time-dependent measurements of light propagation can be used to monitor the fluorescent lifetimes of a uniformly distributed fluorophore in tissues. With proper referencing, frequency-domain measurements of phase-shift, theta, may allow quantitation of fluorescent lifetimes, tau, independent of changes in the local absorption and scattering properties. These results point to a new approach for noninvasive diagnostic monitoring through quantitation of fluorescent lifetime, tau, when the lifetime of the fluorophore is comparable with photon migration times.

Biophysical Phenomena↗

PubMed1994

Computations of time-dependent photon migration for biomedical optical imaging.

In summary, Table II is a listing of the pitfalls and advantages of using Monte Carlo simulations and numerical solution of the diffusion equation to describe photon migration in tissues. Judicious use of these techniques to describe the solution to the forward imaging problem may allow determination of the best theoretical resolution and the smallest detectable volume for the range of optical property differences expected in situ or imposed by contrast agent administration. Furthermore, an understanding of the forward imaging problem through these numerical techniques also contributes to our understanding of the most efficient solution to the inverse imaging problem.

Algorithms↗

PubMedDate not supplied

Multipixel techniques for frequency-domain photon migration imaging.

The ability to map interior optical properties of a highly scattering medium from exterior measurements of light propagation is afforded by optical tomography. In this communication, we describe the problem of optical tomography, the techniques of photon migration measurements necessary to accomplish it, and the development of multipixel measurements for rapid collection of optical signals. These multipixel measurements are shown to provide detection of contrast owing to the optical properties of absorption and fluorescence associated with dye-laden heterogeneities embedded in a tissue-like scattering medium. From these rapid measurements, successful reconstruction of an interior optical property map may now be possible with clinically realistic data acquisition times. Applications for the technology arise for biomedical optical imaging for the in vivo detection of disease and the diagnosis of tissue (bio-) chemistry.

Absorption↗

PubMedDate not supplied

Measurements of multiply scattered light for on-line monitoring of changes in size distribution of cell debris suspension.

Dual wavelength frequency-domain measurements of photon migration (FDPM) are conducted on filtrate samples obtained from an industrial centrifugation process designed to separate Escherichia coli cell debris from the inclusion bodies. FDPM measurements consist of detecting phase delay of intensity-modulated light at 670 and 820 (or 830) nm. Optical properties of isotropic scattering and absorption are obtained from the regression of phase delay data to the optical diffusion equation. We show that the corresponding intensity-based measurements alone cannot provide accurate and independent estimates for these optical properties. However, FDPM-derived scattering coefficients of filtrate solutions (primarily consisting of 0.1-0.2 micrometer E. coli cell debris) are sensitive to approximately 1 vol % of added inclusion bodies (of 1-2 micrometer size). The technique, theory, and future adaptation of FDPM as an on-line monitor to detect the loss of inclusion bodies in centrifugation following homogenization are presented and contrasted to conventional, intensity-based measurements.

Biotechnology↗

PubMedDate not supplied

Developments toward diagnostic breast cancer imaging using near-infrared optical measurements and fluorescent contrast agents.

The use of near-infrared (NIR) light to interrogate deep tissues has enormous potential for molecular-based imaging when coupled with NIR excitable dyes. More than a decade has now passed since the initial proposals for NIR optical tomography for breast cancer screening using time-dependent measurements of light propagation in the breast. Much accomplishment in the development of optical mammography has been demonstrated, most recently in the application of time-domain, frequency-domain, and continuous-wave measurements that depend on endogenous contrast owing to angiogenesis and increased hemoglobin absorbance for contrast. Although exciting and promising, the necessity of angiogenesis-mediated absorption contrast for diagnostic optical mammography minimizes the potential for using NIR techniques to assess sentinel lymph node staging, metastatic spread, and multifocality of breast disease, among other applications. In this review, we summarize the progress made in the development of optical mammography, and focus on the emerging work underway in the use of diagnostic contrast agents for the molecular-based, diagnostic imaging of breast.

Absorption↗

PubMedDate not supplied

Diagnostic imaging of breast cancer using fluorescence-enhanced optical tomography: phantom studies.

Molecular targeting with exogenous near-infrared excitable fluorescent agents using time-dependent imaging techniques may enable diagnostic imaging of breast cancer and prognostic imaging of sentinel lymph nodes within the breast. However, prior to the administration of unproven contrast agents, phantom studies on clinically relevant volumes are essential to assess the benefits of fluorescence-enhanced optical imaging in humans. Diagnostic 3-D fluorescence-enhanced optical tomography is demonstrated using 0.5 to 1 cm(3) single and multiple targets differentiated from their surroundings by indocyanine green (micromolar) in a breast-shaped phantom (10-cm diameter). Fluorescence measurements of referenced ac intensity and phase shift were acquired in response to point illumination measurement geometry using a homodyned intensified charge-coupled device system modulated at 100 MHz. Bayesian reconstructions show artifact-free 3-D images (3857 unknowns) from 3-D boundary surface measurements (126 to 439). In a reflectance geometry appropriate for prognostic imaging of lymph node involvement, fluorescence measurements were likewise acquired from the surface of a semi-infinite phantom (8x8x8 cm(3)) in response to area illumination (12 cm(2)) by excitation light. Tomographic 3-D reconstructions (24,123 unknowns) were recovered from 2-D boundary surface measurements (3194) using the modified truncated Newton's method. These studies represent the first 3-D tomographic images from physiologically relevant geometries for breast imaging.

Algorithms↗