Biomedical subjects

Eva M Sevick-Muraca

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

33 records · Page 2Linked to original sources

PubMed2002

Volume of pharmaceutical powders probed by frequency-domain photon migration measurements of multiply scattered light.

Using probability distribution analysis to describe the propagation of multiply scattered light between a point source and point detector located a known distance apart, mathematical expressions predicting the volume of sampled powder were determined for infinite and semi-infinite powder beds and then compared to experimental measurements of frequency-domain photon migration (FDPM). Our results show that the volume of powder sampled varies with optical properties and, when using FDPM techniques, with modulation frequency. For a typical measurement in lactose powder, the volume of powder sampled by multiply scattered light propagating between a 1000-microm-diameter point source and point detector pair separated by 8 mm is predicted to be 1.8 and 1.5 cm3 at modulated frequencies of 50 and 100 MHz, respectively. Experimental measurements in lactose powder confirm the predictions.

Lactose↗

PubMed2002

Three-dimensional, Bayesian image reconstruction from sparse and noisy data sets: near-infrared fluorescence tomography.

A method for inverting measurements made on the surfaces of tissues for recovery of interior optical property maps is demonstrated for sparse near-infrared (NIR) fluorescence measurement sets on large tissue-simulating volumes with highly variable signal-to-noise ratio. A Bayesian minimum-variance reconstruction algorithm compensates for the spatial variability in signal-to-noise ratio that must be expected to occur in actual NIR contrast-enhanced diagnostic medical imaging. Image reconstruction is demonstrated by using frequency-domain photon migration measurements on 256-cm(3) tissue-mimicking phantoms containing none, one, or two 1-cm(3) heterogeneities with 50- to 100-fold greater concentration of Indocyanine Green dye over background levels. The spatial parameter estimate of absorption owing to the dye was reconstructed from only 160 to 296 surface measurements of emission light at 830 nm in response to incident 785-nm excitation light modulated at 100 MHz. Measurement error of acquired fluence at fluorescent emission wavelengths is shown to be highly variable. Convergence and quality of image reconstructions are improved by Bayesian conditioning incorporating (i) experimentally determined measurement error variance, (ii) recursively updated estimates of parameter uncertainty, and (iii) dynamic zonation. The results demonstrate that, to employ NIR fluorescence-enhanced optical imaging for large volumes, reconstruction approaches must account for the large range of signal-to-noise ratio associated with the measurements.

Analysis of Variance↗

PubMed2002

Investigation of particle interactions in concentrated colloidal suspensions using frequency domain photon migration: monodisperse systems.

Frequency domain photon migration (FDPM) measurements were conducted to assess particle interactions of concentrated, monodisperse, polystyrene samples obtained directly from industry by using multiple scattering light. The angle-integrated static structure factor, S(q), and static structure factor at small wave vector q, S(0), were obtained from FDPM measurements at high volume fractions ranging from 0.05 to 0.3, and were compared with those obtained from the monodisperse hard sphere Percus-Yevick (HSPY) model. Effects of different colloid sizes on structure factor evaluated at two different wavelengths were also investigated. Results show that the monodisperse HSPY model is suitable for accounting for particle interactions and local microstructures in these colloidal suspensions. Upon using the HSPY model, particle sizes of polystyrene suspensions were recovered from FDPM measurements at high volume fractions (up to 0.3), which agree well with the DLS measurement of diluted sample ( approximately 0.001). The study of polydispersity effect shows that the FDPM method can be successfully used for recovering the mean particle size of polydisperse colloidal suspension with low polydispersity (<16%) under the assumption of monodisperse hard sphere systems.

Journal Article↗

PubMed2002

Fluorescence lifetime spectroscopy in multiply scattering media with dyes exhibiting multiexponential decay kinetics.

To investigate fluorescence lifetime spectroscopy in tissue-like scattering, measurements of phase modulation as a function of modulation frequency were made using two fluorescent dyes exhibiting single exponential decay kinetics in a 2% intralipid solution. To experimentally simulate fluorescence multiexponential decay kinetics, we varied the concentration ratios of the two dyes, 3,3-diethylthiatricarbocyanine iodide and indocynanine green (ICG), which exhibit distinctly different lifetimes of 1.33 and 0.57 ns, respectively. The experimental results were then compared with values predicted using the optical diffusion equation incorporating 1) biexponential decay, 2) average of the biexponential decay, as well as 3) stretched exponential decay kinetic models to describe kinetics owing to independent and quenched relaxation of the two dyes. Our results show that while all kinetic models could describe phase-modulation data in nonscattering solution, when incorporated into the diffusion equation, the kinetic parameters failed to likewise predict phase-modulation data in scattering solutions. We attribute the results to the insensitivity of phase-modulation measurements in nonscattering solutions and the inaccuracy of the derived kinetic parameters. Our results suggest the high sensitivity of phase-modulation measurements in scattering solutions may provide greater opportunities for fluorescence lifetime spectroscopy.

Benzothiazoles↗

PubMed2002

Fluorescence-enhanced, near infrared diagnostic imaging with contrast agents.

The deep tissue propagation of near-infrared (NIR) light between 700-900 nm offers new opportunities for diagnostic imaging when employing sensitive detection techniques and NIR excitable fluorescent agents that target and report disease and metabolism. Herein, we highlight approaches for illuminating tissues and monitoring the re-emitted fluorescence for tomographic reconstruction, strategies for developing fluorescent dye constructs, and clinical opportunities for fluorescence-enhanced NIR optical imaging.

Amino Acid Sequence↗

PubMed2002

Three-dimensional fluorescence enhanced optical tomography using referenced frequency-domain photon migration measurements at emission and excitation wavelengths.

The ultimate success of near-infrared optical tomography rests on the precise measurement of light propagation within tissues or random media, the accurate prediction of these measurements from a light propagation model, and an efficient three-dimensional solution of the inverse imaging problem. To date, optical tomography algorithms have focused on frequency-domain photon migration (FDPM) measurements of phase-delay and amplitude attenuation, which are reported relative to the incident light, even though phase-delay and amplitude of incident light are nearly impossible to measure directly. In this contribution, we examine referenced, fluorescence-enhanced frequency-domain photon migration measured at excitation and/or emission wavelengths and report on a measurement strategy to minimize measurement and calibration error for efficient coupling of data to a distorted Born iterative imaging algorithm. We examine three referencing approaches and develop associated inversion algorithms for (1) normalizing detected emission FDPM data to the predicted emission wave arising from a homogeneous medium, (2) referencing detected emission FDPM data to that detected at a reference point, and (3) referencing detected emission FDPM data to detected excitation FDPM data detected at a reference point. Our results show the latter approach to be practical while reducing the nonlinearity of the inverse problem. Finally, in light of our results, we demonstrate the method for eliminating the influence of source strength and instrument functions for effective fluorescence-enhanced optical tomography using FDPM.

Computer Simulation↗

PubMedDate not supplied

Fluorescence lifetime spectroscopy of a pH-sensitive dye encapsulated in hydrogel beads.

A pH-sensing dye, carboxy seminaphthofluorescein-1 (C-SNAFL-1), was immobilized in poly(ethylene glycol) (PEG) microparticles via ester-amine reaction. Following photopolymerization, the hydrogel particles were then immersed in buffered pH solutions of varying pH with added polystyrene. Measurements of phase shift and amplitude attenuation of the generated and multiply scattered fluorescent light were attained as a function of modulation frequency of the incident excitation light. Upon regressing the measured data to the coupled optical diffusion equations, the average lifetimes of protonated and deprotonated forms of C-SNAFL-1 were obtained and compared to the values acquired from conventional fluorescence lifetime spectroscopy in nonscattering media. The results demonstrate the ability to perform analyte sensing with fluorescence lifetime without the confounding effect of fluorophore loading or the use of a "reference" measurement within multiply scattering systems. When extended to the immobilized fluorophore-enzymatic systems, fluorescence lifetime spectroscopy with multiply scattered light may provide a new ultrasensitive approach for analyte or toxin screening.

Algorithms↗

PubMedDate not supplied

Determination of optical properties in semi-infinite turbid media using imaging measurements of frequency-domain photon migration obtained with an intensified charge-coupled device.

Frequency-domain photon migration measurements across the surface of a tissue-mimicking, semi-infinite phantom are acquired via an intensified charge-coupled device (ICCD) detection system and used in conjunction with the diffusion approximation to determine the optical properties. The absorption and reduced scattering coefficients are determined least accurately when relative measurements of average light intensity I(rel)dc are employed either alone or in a combination with relative modulation amplitude data I(rel)ac and/or relative phase shift data theta(rel). The absorption and reduced scattering coefficients are found accurate to within 15 and 11%, respectively, of the values obtained from standard single-pixel measurements when theta(rel) measurements are employed alone or in combination with I(rel)ac data.

Algorithms↗

PubMedDate not supplied

Quantifying molecular specificity of alphavbeta3 integrin-targeted optical contrast agents with dynamic optical imaging.

Dynamic fluorescence images were obtained from a subcutaneous human Kaposi's sarcoma tumor (KS1767) model immediately following the intravenous injection of an integrin-targeting cyanine dye conjugate, Cy5.5-c(KRGDf). The fluorescence images, acquired via an intensified charge-coupled device detection system, were used in conjunction with a pharmacokinetic (PK) model to determine kinetic properties of target binding in the presence and absence of a competitive ligand, free c(KRGDf). The results indicate that the conjugate dye behaves similarly in normal tissue to the free Cy5.5 dye while it possesses increased uptake in tumor tissue. The change in pharmacokinetic parameters obtained from dynamic imaging of Cy5.5-c(KRGDf) after administration of c(KRGDf) as a competitive ligand to the integrin receptor suggests that (i) the increased uptake of Cy5.5-c(KRGDf) is molecularly specific and that (ii) receptor turnover occurs within 24 h. In addition, PK analysis enables quantification of an in vivo c(KRGDf) binding constant attributable to integrin binding. In vivo pharmacokinetic analysis based on rapid and dynamic optical imaging may be potentially useful for evaluating the presence and turnover rate of disease markers that are potential targets of molecular medicine.

Animals↗

PubMedDate not supplied

Quality analysis of in vivo near-infrared fluorescence and conventional gamma images acquired using a dual-labeled tumor-targeting probe.

The cyclic peptide, cyclopentapeptide cyclo(lys-Arg-Gly-Asp-phe) (c(KRGDf)), which is known to target alpha(v)beta3 integrin, is dual-labeled with a radiotracer, (111)indium, for gamma scintigraphy as well as with a near-infrared dye, IRDye800, for continuous-wave (cw) imaging of alpha(v)beta3 positive human M21 melanoma in xenografts. Twenty-four hours after administration of the dual-labeled peptide at a dose equivalent to 90 microCi of (111)In and 5 nmol of near-infrared (NIR) dye, whole-body gamma scintigraphy and cw imaging was conducted. Image acquisition time was 15 min for the gamma scintigraphy images and 800 ms for the optical images acquired using an NIR sensitive intensified charge-coupled device. The results show that while the target-to-background ratio (TBR) of nuclear and optical imaging were similar for surface regions of interest and consistent with the origin of gamma and NIR radiation from a common targeted peptide, the signal-to-noise ratio (SNR) was significantly higher for optical than nuclear imaging. Furthermore, an analysis of SNR versus contrast showed greater sensitivity of optical over nuclear imaging for the subcutaneous tumor targets. While tomographic reconstructions are necessary to probe TBR, SNR, and contrast for interior tissues, this work demonstrates for the first time the direct comparison of molecular optical and planar nuclear imaging for surface and subsurface cancers.

Animals↗

PubMedDate not supplied

Fluorescence-enhanced optical tomography of a large tissue phantom using point illumination geometries.

We demonstrate fluorescence-enhanced optical imaging of single and multiple fluorescent targets within a large (approximately 1081 cm3) phantom using frequency-domain photon migration measurements of fluorescence collected at individual points in response to illumination of excitation light at individual points on the boundary. The tissue phantom was filled with a 1% lipid solution with and without 0.01 microM Indocyanine Green (ICG) and targets consisted of vials filled with the 1% lipid containing 1-2.5 microM ICG. Measurements were acquired using a modulated intensified CCD imaging system under different experimental conditions. For 3-D image reconstruction, the gradient-based penalty modified barrier function (PMBF) method with simple bounds constrained truncated Newton with trust region method (CONTN) was used. Targets of 0.5, 0.6, and 1.0 cm3 at depths of 1.4-2.8 cm from the phantom surface were tomographically reconstructed. This work demonstrates the practicality of fluorescence-enhanced tomography in clinically relevant volumes.

Breast Neoplasms↗

PubMedDate not supplied

Near-infrared fluorescence optical imaging and tomography.

The advent of recent advances in near-infrared laser diodes and fast electro-optic detection has spawned a new research field of diagnostic spectroscopy and imaging based on targeting and reporting exogenous fluorescent agents. This review seeks to concisely address the physics, instrumentation, advancements in tomography, and near-infrared fluorescent contrast agent development that promises selective and specific molecular targeting of diseased tissues. As an example of one area of the field, recent work focusing on pharmacokinetic analysis of fluorophores targeting the epidermal growth factor receptor (EGFR) is presented in a human breast cancer xenograft mouse model to demonstrate specificity of molecularly targeted contrast agents. Finally, a critical evaluation of the limitations and the opportunities for future translation of fluorescence-enhanced optical imaging of deep tissues is presented.

Animals↗

PubMedDate not supplied

Imaging dose-dependent pharmacokinetics of an RGD-fluorescent dye conjugate targeted to alpha v beta 3 receptor expressed in Kaposi's sarcoma.

Dynamic fluorescence images were obtained from xenografts bearing a subcutaneous human Kaposi's sarcoma (KS1767) immediately following the intravenous injection of an integrin-receptor targeting Cy5.5-c(KRGDf) at a dose ranging from 0.75 to 6 nmol/mouse. The fluorescence images were acquired using an intensified charge-coupled device system and were analyzed with a three-compartment pharmacokinetic (PK) model to determine uptake parameters in the tumor and normal tissue regions of interest as a function of administered dose. Our results show that the uptake of Cy5.5-c(KRGDf) in tumor regions were: (i) significantly greater than the contralateral normal tissue regions; (ii) linearly increased with dose of Cy5.5-c(KRGDf) up to 1.5 nmol/mouse; and (iii) blocked by preinjection of c(KRGDf). Above doses of 1.5 nmol/mouse, the uptake no longer increased with dose, suggesting integrin receptor saturation. In normal tissues, the PK uptake parameters were not influenced by Cy5.5-c(KRGDf) dose nor by the preadministration of c(KRGDf).

Animals↗

PubMedDate not supplied

Improved excitation light rejection enhances small-animal fluorescent optical imaging.

Small-animal fluorescence-enhanced imaging involves the detection of weak fluorescent signals emanating from nanomolar to picomolar concentrations of exogenous or endogenously produced fluorophore concurrent with the rejection of an overwhelmingly large component of backscattered excitation light. The elimination of the back-reflected excitation light of the collected signal remains a major and often unrecognized challenge for further reducing the noise floor and increasing sensitivity of small-animal fluorescence imaging. Herein, we show that the combination of three-cavity interference and holographic super notch filters with appropriate imaging lenses to collimate light improves rejection of excitation light, enabling more accurate imaging. To assess excitation leakage, the "out-of-band (S(lambda x))" to "in-band (S(lambda m) - S(lambda x))" signal ratio from phantom studies and the target-to-background ratio (TBR) from in vivo animal imaging was acquired with and without collimating optics. The addition of collimating optics resulted in a 51% to 75% reduction in the ratio of (S(lambda x))/(S(lambda m) - S(lambda x)) for the phantom studies and an improvement of TBR from 11% to 31% and of signal-to-noise ratio from 11% to 142% for an integrin-targeting conjugate in human glioma xenografts.

Animals↗

PubMedDate not supplied

Measurements of FRET in a glucose-sensitive affinity system with frequency-domain lifetime spectroscopy.

We report measurements of fluorescence resonance energy transfer (FRET) for glucose sensing in an established concanavalin A-dextran affinity system using frequency-domain lifetime spectroscopy. A dextran (MW 2,000,000) labeled with a small fluorescent donor molecule, Alexa Fluor 568, was used to competitively bind to a sugar-binding protein, concanavalin A, labeled with acceptor molecule, Alexa Fluor 647, in the presence of glucose. The FRET-quenching kinetics of the donor were analyzed from frequency-domain measurements as a function of both glucose and acceptor-protein concentrations using a Förster-type decay kinetics model. The results show that the frequency-domain measurements and donor decay kinetics can quantitatively indicate changes in the competitive binding of 0.09 microM dextran to labeled concanavalin A at a solution concentration of 10.67 microM in the presence of glucose at concentrations ranging from 0 to 224 mg/dL.

Binding, Competitive↗