Biomedical subjects

Michael S Feld

Publications and source records attributed to Michael S Feld.

34 records · Page 2Linked to original sources

PubMed2003

Optical imaging of the cervix.

Recent advances in fiber optics, sources and detectors, imaging, and computer-controlled instrumentation have stimulated a period of unprecedented growth in the development of photonics technologies for a wide variety of diagnostic and therapeutic clinical applications. These include the application of quantitative optical spectroscopy and imaging for the detection of precancerous lesions in the uterine cervix, a topic of interest at the Second International Conference on Cervical Cancer, which was held April 11-14, 2002. Investigators have applied the Littenberg method of emerging technology assessment to new optical methods used to detect cervical neoplasia. Currently, such technologies as fluorescence spectroscopy (the combination of fluorescence and diffuse reflectance spectroscopy), tri-modal spectroscopy, and light-scattering spectroscopy that probe the spectral characteristics of tissue are being investigated. Optical technologies that create images of subcellular structure without biopsy subsequent to pathology that currently are under investigation include in vivo confocal imaging and optical coherence tomography. Numerous small studies have demonstrated the potential of these optical technologies. What remains to be elucidated are the fundamental biophysical origins of variations in remitted optical signals between normal and dysplastic tissue. Large multicenter randomized controlled trials are needed to confirm the detection and imaging capabilities of optical technology. Furthermore, the development of contrast agents that could boost detection with these technologies is needed, and basic biologic characterization of signals should be pursued. Applying the Littenberg assessment will help ensure that superior, not simply alternative, technologies are implemented.

Cervix Uteri↗

PubMed2003

In situ detection of neoplastic transformation and chemopreventive effects in rat esophagus epithelium using angle-resolved low-coherence interferometry.

We present a quantitative study of the nuclear morphometry of epithelial cells in an animal model of esophageal carcinogenesis. Changes in the size and texture of cell nuclei as a result of neoplastic transformation and chemopreventive action are observed in situ using a new optical technique, angle-resolved low-coherence interferometry (a/LCI). The capabilities of a/LCI are demonstrated via quantitative in situ measurements of the nuclear morphometry of basal epithelial cells, approximately 50-100 microm beneath the tissue surface without the need for exogenous contrast agents or tissue fixation. The measurements quantify changes in nuclear size, characterized by average diameter, and nuclear texture, characterized by fractal dimension of the subcellular structures. Using this technique, we observed changes in the morphometry of rat esophageal epithelial cells in response to treatment with the carcinogen N-nitrosomethylbenzylamine. In addition, morphometric changes were observed in the esophagi of rats treated with N-nitrosomethylbenzylamine and two chemopreventive agents, difluoromethylornithine and perillyl alcohol. These agents induced either apoptosis in the basal epithelium (difluoromethylornithine) or both apoptosis and vacuolation of basal epithelial cells (perillyl alcohol). Vacuolation was associated with cellular toxicity. The light-scattering measurements were compared with histological images of the same tissues. The potential of a/LCI as a noninvasive means to investigate the development of epithelial neoplasia and for tracking the efficacy of chemopreventive agents appears high. This technique also may provide a new screening tool for intraepithelial neoplasia.

Animals↗

PubMed2003

Spectroscopic detection and evaluation of morphologic and biochemical changes in early human oral carcinoma.

BACKGROUND: Understanding the development and progression of head and neck squamous cell carcinoma is key in the quest for the early diagnosis and prevention of this type of malignancy. The current study correlated early biochemical and histologic changes in oral tissue with spectral features in fluorescence, reflectance, and light scattering spectra acquired in vivo to diagnose early stages of oral malignancies. METHODS: A total of 91 tissue sites from 15 patients with varying degrees of malignancy (normal, dysplastic, and cancerous sites) and 8 healthy volunteers were analyzed with 3 spectroscopic techniques. Direct biochemical information regarding oral tissue native fluorophores was obtained with intrinsic fluorescence spectroscopy by fitting a linear combination of collagen and the reduced form of nicotinamide adenine dinucleotide (NADH) fluorescence spectra to the intrinsic tissue fluorescence spectra excited with 337 nanometer (nm) and 358-nm laser light. Diffuse reflectance spectroscopy was used to provide information regarding tissue absorption and structure, such as hemoglobin concentration and stroma density, by measuring the wavelength-dependent absorption and scattering coefficients. By subtracting the diffusely reflected component from the measured reflectance, light scattering spectroscopy (LSS) information resulting from single backscattering from epithelial cell nuclei was obtained. LSS provides information concerning the size distribution of cell nuclei. RESULTS: These optically extracted tissue parameters provide biochemical or structural information in vivo without the need for tissue excision, and can be used to diagnose tissue abnormalities. By combining the information provided by the three techniques, a method known as trimodal spectroscopy, a sensitivity and specificity of 96% and 96%, respectively, in distinguishing cancerous/dysplastic (mild, moderate, and severe) from normal tissue was achieved. In addition, the authors were able to distinguish dysplastic from cancerous tissue with a sensitivity of 64% and a specificity of 90%. CONCLUSIONS: The results of the current study demonstrated that Trimodal spectroscopy is a highly sensitive and specific technique with which to diagnose tissue abnormalities.

Carcinoma↗

PubMed2002

Identifying microcalcifications in benign and malignant breast lesions by probing differences in their chemical composition using Raman spectroscopy.

We have applied Raman spectroscopy to analyze the chemical composition of microcalcifications occurring in benign and malignant lesions in the human breast. Microcalcifications were initially separated into two categories based on their Raman spectrum: type I, calcium oxalate dihydrate, and type II, calcium hydroxyapatite. Type I microcalcifications were diagnosed as benign, whereas type II were subdivided into benign and malignant categories using principal component analysis, a statistical technique. Although type II microcalcifications are primarily composed of calcium hydroxyapatite, they also contain trace amounts of several biological impurities. Using principal component analysis, we were able to highlight subtle chemical differences in type II microcalcifications that correlate with breast disease. On the basis of these results, we believe that type II microcalcifications formed in benign ducts typically contain a larger amount of calcium carbonate and a smaller amount of protein than those formed in malignant ducts. Using this diagnostic strategy, we were able to distinguish microcalcifications occurring in benign and malignant ducts with a sensitivity of 88% and a specificity of 93%. This is a significant improvement over current X-ray mammography techniques, which are unable to reliably differentiate microcalcifications in benign and malignant breast lesions.

Adult↗

PubMed2002

NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes.

During the development of neoplasia, epithelial tissues undergo biochemical and structural changes that can manifest in tissue fluorescence. There have been several reports on different in vivo fluorescence characteristics between normal and precancerous (dysplastic) tissues. However, it has been difficult to identify and quantify the origins of these changes, mainly because of distortions introduced in measured tissue fluorescence spectra by tissue scattering and absorption. Such distortions can be removed by combining information in simultaneously measured fluorescence and reflectance spectra. Thus, we can recover the intrinsic (undistorted) tissue fluorescence. In this report, we show that extraction of the intrinsic fluorescence allows us: (a) to determine the fluorescence spectra of NAD(P)H and collagen in an in vivo environment, and (b) to use these NAD(P)H and collagen spectra to describe, quantitatively, diagnostically significant biochemical changes between normal and dysplastic tissues. Specifically, by analyzing intrinsic fluorescence of human epithelial tissue as it becomes deoxygenated in vivo, we can resolve the fluorescence spectra of NAD(P)H and collagen, two of the major tissue fluorophores. This is important because fluorescence depends on the local environment of the chromophore. Then, we extract the intrinsic fluorescence spectra of sites from 35 patients with suspected cervical lesions and 7 patients with Barrett's esophagus and describe them accurately as a linear combination of NAD(P)H and collagen contributions. In both tissue cases, we find that low collagen and high NAD(P)H fluorescence characterizes the high-grade dysplastic lesions when compared with nondysplastic tissues. These data present evidence for the presence of detectable levels of NAD(P)H fluorescence in human epithelial tissues in an in vivo setting and demonstrate that NAD(P)H and collagen may be used as quantitative fluorescence biomarkers for in vivo detection of dysplasia in the cervix and the esophagus.

Barrett Esophagus↗

PubMed2002

Model-based biological Raman spectral imaging.

Raman spectral imaging is a powerful tool for determining chemical information in a biological specimen. The challenge is to condense the large amount of spectral information into an easily visualized form with high information content. Researchers have applied a range of techniques, from peak-height ratios to sophisticated models, to produce interpretable Raman images. The purpose of this article is to review some of the more common imaging approaches, in particular principal components analysis, multivariate curve resolution, and Euclidean distance, as well as to present a new technique, morphological modeling. How to best extract meaningful chemical information using each imaging approach will be discussed and examples of images produced with each will be shown.

Algorithms↗

PubMed2002

Cellular organization and substructure measured using angle-resolved low-coherence interferometry.

We measure the organization and substructure of HT29 epithelial cells in a monolayer using angle-resolved low-coherence interferometry. This new technique probes cellular structure by measuring scattered light, as in flow cytometry, but offers an advantage in that the structure can be examined in situ, avoiding the need to disrupt the cell monolayer. We determine the size distribution of the cell nuclei by fitting measured light-scattering spectra to the predictions of Mie theory. In addition, we obtain information about the cellular organization and substructure by examining the spatial correlations within the monolayer. A remarkable finding is that the spatial correlations over small length scales take the form of an inverse power law, indicating the fractal nature of the packing of the subcellular structures. We also identify spatial correlations on a scale large compared with the size of a cell, indicating an overlying order within the monolayer.

Biophysics↗

PubMed2002

Trimodal spectroscopy for the detection and characterization of cervical precancers in vivo.

OBJECTIVE: The objective of this study was to assess the potential of 3 spectroscopic techniques (intrinsic fluorescence, diffuse reflectance, and light scattering) individually and in combination (trimodal spectroscopy) for the detection of cervical squamous intraepithelial lesions. STUDY DESIGN: The study was conducted with 44 patients who underwent colposcopy for the evaluation of an abnormal Papanicolaou smear. Fluorescence and reflectance spectra were collected from colposcopically normal and abnormal sites and analyzed to extract quantitative information about tissue biochemistry and morphologic condition. This information was compared with histopathologic classification, and diagnostic algorithms were developed and validated with the use of logistic regression and cross-validation. RESULTS: Diagnostically significant differences exist in the composition of fluorescing biochemicals, the scattering properties, and the epithelial cell nuclear morphology of cervical squamous intraepithelial lesions and non-squamous intraepithelial lesions. Trimodal spectroscopy is a superior tool for the detection of cervical squamous intraepithelial lesions than any 1 of the techniques alone. CONCLUSION: Trimodal spectroscopy has the potential to improve the in vivo detection of precancerous cervical changes.

Diagnosis, Differential↗

PubMed2002

Determination of particle size by using the angular distribution of backscattered light as measured with low-coherence interferometry.

We employ a novel interferometer to measure the angular distribution of light backscattered by a turbid medium. Through comparison of the measured data with the predictions of Mie theory, we are able to determine the size of the scatterers comprising the medium with subwavelength precision. As the technique is based on low-coherence interferometry, we are able to examine the evolution of the angular distribution of scattered light as it propagates into the medium. The effects of multiple scattering as a function of penetration depth in the medium are analyzed. We also present various considerations for extending this technique to determining structural information in biological tissues, such as the effects of a distribution of particle sizes and the need to average out speckle contributions.

Interferometry↗

PubMedDate not supplied

Raman spectroscopy for noninvasive glucose measurements.

We report the first successful study of the use of Raman spectroscopy for quantitative, noninvasive ("transcutaneous") measurement of blood analytes, using glucose as an example. As an initial evaluation of the ability of Raman spectroscopy to measure glucose transcutaneously, we studied 17 healthy human subjects whose blood glucose levels were elevated over a period of 2-3 h using a standard glucose tolerance test protocol. During the test, 461 Raman spectra were collected transcutaneously along with glucose reference values provided by standard capillary blood analysis. A partial least squares calibration was created from the data from each subject and validated using leave-one-out cross validation. The mean absolute errors for each subject were 7.8%+/-1.8% (mean+/-std) with R2 values of 0.83+/-0.10. We provide spectral evidence that the glucose spectrum is an important part of the calibrations by analysis of the calibration regression vectors.

Blood Glucose↗

PubMedDate not supplied

Real-time Raman system for in vivo disease diagnosis.

Raman spectroscopy has been well established as a powerful in vitro method for studying biological tissue and diagnosing disease. The recent development of efficient, high-throughput, low-background optical fiber Raman probes provides, for the first time, the opportunity to obtain real-time performance in the clinic. We present an instrument for in vivo tissue analysis which is capable of collecting and processing Raman spectra in less than 2 s. This is the first demonstration that data acquisition, analysis, and diagnostics can be performed in clinically relevant times. The instrument is designed to work with the new Raman probes and includes custom written LabVIEW and Matlab programs to provide accurate spectral calibration, analysis, and diagnosis along with important safety features related to laser exposure. The real-time capabilities of the system were demonstrated in vivo during femoral bypass and breast lumpectomy surgeries. Such a system will greatly facilitate the adoption of Raman spectroscopy into clinical research and practice.

Algorithms↗

PubMedDate not supplied

Prospective grading of neoplastic change in rat esophagus epithelium using angle-resolved low-coherence interferometry.

Angle-resolved low-coherence interferometry (a/LCI) is used to obtain quantitative, depth-resolved nuclear morphology measurements. We compare the average diameter and texture of cell nuclei in rat esophagus epithelial tissue to grading criteria established in a previous a/LCI study to prospectively grade neoplastic progression. We exploit the depth resolution of a/LCI to exclusively examine the basal layer of the epithelium, approximately 50 to 100 microm beneath the tissue surface, without the need for exogenous contrast agents, tissue sectioning, or fixation. The results of two studies are presented that compare the performance of two a/LCI modalities. Overall, the combined studies show 91% sensitivity and 97% specificity for detecting dysplasia, using histopathology as the standard. In addition, the studies enable the effects of dietary chemopreventive agents, difluoromethylornithine (DFMO) and curcumin, to be assessed by observing modulation in the incidence of neoplastic change. We demonstrate that a/LCI is highly effective for monitoring neoplastic change and can be applied to assessing the efficacy of chemopreventive agents in the rat esophagus.

Animals↗

PubMedDate not supplied

Erythrocyte structure and dynamics quantified by Hilbert phase microscopy.

We present a new quantitative method for investigating red blood cell morphology and dynamics. The instrument integrates quantitative phase microscopy with an inverted microscope, which makes it particularly suitable for the noninvasive assessment of live erythrocytes. In particular, we demonstrate the ability of this approach to quantify noninvasively cell volume and dynamic morphology. The subnanometer path-length sensitivity at the millisecond time scales is exemplified by measuring the hemoglobin flow out of the cell during hemolysis.

Cell Size↗

PubMedDate not supplied

Detection of morphological markers of vulnerable atherosclerotic plaque using multimodal spectroscopy.

Vulnerable plaques, which are responsible for most acute ischemic events, are presently invisible to x-ray angiography. Their primary morphological features include a thin or ulcerated fibrous cap, a large necrotic core, superficial foam cells, and intraplaque hemorrhage. We present evidence that multimodal spectroscopy (MMS), a novel method that combines diffuse reflectance spectroscopy (DRS), intrinsic fluorescence spectroscopy (IFS), and Raman spectroscopy (RS), can detect these markers of plaque vulnerability. To test this concept, we perform an MMS feasibility study on 17 human carotid artery specimens. Following the acquisition of spectra, each specimen is histologically evaluated. Two parameters from DRS, hemoglobin concentration and a scattering parameter, are used to detect intraplaque hemorrhage and foam cells; an IFS parameter that relates to the amount of collagen in the topmost layers of the tissue is used to detect the presence of a thin fibrous cap; and an RS parameter related to the amount of cholesterol and necrotic material is used to detect necrotic core. Taken together, these spectral parameters can generally identify the vulnerable plaques. The results indicate that MMS provides depth-sensitive and complementary morphological information about plaque composition. A prospective in vivo study will be conducted to validate these findings.

Algorithms↗

PubMedDate not supplied

In vivo Raman spectral pathology of human atherosclerosis and vulnerable plaque.

The rupture of vulnerable atherosclerotic plaque accounts for the majority of clinically significant acute cardiovascular events. Because stability of these culprit lesions is directly related to chemical and morphological composition, Raman spectroscopy may be a useful technique for their study. Recent developments in optical fiber probe technology have allowed for the real-time in vivo Raman spectroscopic characterization of human atherosclerotic plaque demonstrated in this work. We spectroscopically examine 74 sites during carotid endarterectomy and femoral artery bypass surgeries. Of these, 34 are surgically biopsied and examined histologically. Excellent signal-to-noise ratio spectra are obtained in only 1 s and fit with an established model, demonstrating accurate tissue characterization. We also report the first evidence that Raman spectroscopy has the potential to identify vulnerable plaque, achieving a sensitivity and specificity of 79 and 85%, respectively. These initial findings indicate that Raman spectroscopy has the potential to be a clinically relevant diagnostic tool for studying cardiovascular disease.

Algorithms↗

PubMedDate not supplied

Observation of dynamic subdomains in red blood cells.

We quantify the nanoscale structure and low-frequency dynamics associated with live red blood cells. The membrane displacements are measured using quantitative phase images provided by Fourier phase microscopy, with an average path-length stability of 0.75 nm over 45 min. The results reveal the existence of dynamic, independent subdomains across the cells that fluctuate at various dominant frequencies.

Cell Movement↗