Unraveling the puzzles of spectroscopy-based non-invasive blood glucose detection

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2011.Cataloged from PDF version of thesis.Includes bibliographical references.Disorders of glucose homeostasis, including types 1 and 2 diabetes, represent a leading cause of morbidity and mortality worldwide. Diagnosis and therapeutic monitoring of diabetes requires direct measurement of blood glucose. Regardless of the clinical test performed, however, withdrawal of blood is currently required for measurement of blood glucose levels. Non-invasive measurement of blood glucose levels is highly desired, given the large number of diabetics who must undergo glucose testing several times each day. In this context, near-infrared (NIR) Raman spectroscopy has shown substantial promise by providing successful predictions of glucose at physiologically relevant concentrations in vitro and even in individual human volunteers at single sittings. Nevertheless, prospective application of a spectroscopic calibration model - over a larger population or over several sittings - has proven to be challenging. This thesis investigates the optical and physiological challenges that impede calibration transfer by introducing non-analyte specific variances. Specifically, we present major advances in four research directions. First, the effects of sample-to-sample turbidity induced variations in quantitative spectroscopy are studied. To account for these variations, a novel method, based on the photon migration theory, is proposed. We demonstrate that the proposed method can extract intrinsic line shapes and intensity information from Raman spectra acquired in a turbid medium thereby improving quantitative predictions significantly. Second, we quantify the sensitivity of Raman calibration models to endogenous fluorescence and its temporal quenching. Application of shifted subtracted Raman spectroscopy is proposed to reduce the possibility of spurious models developed on the basis of chance correlation between the concentration dataset and quenched fluorescence levels. Third, we solve the problem of physiological lag between blood and interstitial fluid glucose levels, which creates inconsistencies in calibration, where blood glucose measurements are used as reference but the acquired spectra are indicative of ISF glucose levels. To overcome this problem, we introduce a mass transfer-based concentration correction scheme and demonstrate its effectiveness in clinical studies. Finally, we propose a new design for fabricating a handheld Raman glucose monitor by employing excitation and detection of wavelengths selected on the basis of their spectral information content. Based on the advances in instrumentation and methodology outlined in this thesis, we anticipate that our current clinical studies will establish the viability of Raman spectroscopy for non-invasive blood glucose detection.by Ishan Barman.Ph.D

Effect of permeation of discharge characteristics of capacitive deionization process

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2007."June 2007."Includes bibliographical references (leaves 88-90).Cost-effective desalination of seawater can be a panacea for the growing freshwater crisis that ranks alongside the problems of shortage of viable energy resources and global warming in terms of its frightening global spread and magnitude. However, the energy guzzling nature of the existing desalination technologies has resulted in very limited relief characterized by a meager 0.3% contribution to the annual water use. In recent years, capacitive deionization (CDI) has been reported to potentially solve some of the crucial issues that have plagued the classical desalination processes. CDI is a low-pressure, non-membrane desalination technology that employs the basic electrochemical principle of adsorbing ions in a capacitive fashion to high surface-area electrodes such that the outgoing stream becomes devoid of the ions that were present in the incoming stream. Although the power efficiency of CDI is nearly an order-of-magnitude superior to the existing processes, it is plagued by the problem of low water recovery ratio. The costs of pumping and pre- and post-treatment of water added to the rising costs of surface water makes maximizing the recovery ratio a priority. Moreover, the throughput of the plant is related to the water recovery ratio. To drastically reduce the problem of low water recovery ratio while still maintaining the sizeable power consumption advantage of the CDI process, we propose a capacitive deionization process with permeating flow discharge (PFD). In PFD, the waste water is permeated through the porous electrodes rather than flowing in-between the electrodes as is the case in the conventional axial flow discharge (AFD) process.(cont.) We hypothesize that the rate of removal of ions from a channel setup is higher for a process that is influenced by solvent drag (PFD) than for one which is diffusion limited (AFD), given the same flow conditions. A table-top setup, designed to simulate the AFD and PFD processes, is used to obtain precise experimental evidence for the ion removal rate for each process. A mathematical model based on unsteady convection-diffusion process for AFD and membrane transport process for PFD is presented. We find that over smaller time scales, permeating flow is much more efficient in removing the ions detached from the electrical double layer in the porous electrode. Based on our experimental observations, we observe that the use of the PFD process, under conventional operational conditions, can cause a discharge time reduction by at least a factor of two. Numerical simulations carried out on the basis of this model are shown to compare favorably with the experimental observations. The model predicts that the reduction in discharge time translates to an increase in water recovery ratio by approximately 30 percent. Moreover, the clear superiority in power efficiency is not surrendered by employing this new scheme.by Ishan Barman.S.M

Leveraging coffee‐ring effect on plasmonic paper substrate for sensitive analyte detection using Raman spectroscopy

Raman spectroscopy has demonstrated immense promise as a molecular fingerprinting tool in biomedical diagnostics. However, the utility of conventional Raman scattering for ultrasensitive measurements of biofluids is limited by intrinsically weak signals and has spurred advances in and wider applications of plasmon‐enhanced measurements. Here, we propose a label‐free methodology that leverages drop coating deposition on a silver ink‐based plasmonic paper substrate with tunable hydrophobic attributes to combine two distinct sources of enhancement, namely, solute preconcentration and excitation of localized surface plasmons. The facile modulation of the hydrophobicity of the plasmonic silver paper facilitates investigations into the coffee‐ring effect that results from the interplay of contact line pinning, solvent evaporation, and capillary flow. We show that the Raman spectra acquired from the hydrated ring deposits show clear enhancement beyond that obtained from surface‐enhancement owing to the presence of the silver nanofilm. In light of the superior sensitivity and lack of substantive sample preparation requirements, our findings open the door for a complementary low‐cost paper‐based analytical device for molecular sensing.We propose a label‐free analytical tool that leverages drop coating deposition on a silver ink‐based plasmonic paper substrate to combine two distinct sources of enhancement for Raman scattering signals. The facile modulation of the hydrophobicity of the plasmonic silver paper facilitates investigations into the coffee‐ring effect that results from the interplay of contact line pinning, solvent evaporation, and capillary flow. Raman spectra acquired show clear enhancement beyond that obtained from surface‐enhancement owing to the presence of the silver nanofilm.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146368/1/jrs5415_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146368/2/jrs5415.pd

Non-Gated Laser Induced Breakdown Spectroscopy Provides a Powerful Segmentation Tool on Concomitant Treatment of Characteristic and Continuum Emission

We demonstrate the application of non-gated laser induced breakdown spectroscopy (LIBS) for characterization and classification of organic materials with similar chemical composition. While use of such a system introduces substantive continuum background in the spectral dataset, we show that appropriate treatment of the continuum and characteristic emission results in accurate discrimination of pharmaceutical formulations of similar stoichiometry. Specifically, our results suggest that near-perfect classification can be obtained by employing suitable multivariate analysis on the acquired spectra, without prior removal of the continuum background. Indeed, we conjecture that pre-processing in the form of background removal may introduce spurious features in the signal. Our findings in this report significantly advance the prior results in time-integrated LIBS application and suggest the possibility of a portable, non-gated LIBS system as a process analytical tool, given its simple instrumentation needs, real-time capability and lack of sample preparation requirements.National Institute for Biomedical Imaging and Bioengineering (U.S.) (9P41EB015871-26A1

Raman Spectroscopy Provides a Powerful Diagnostic Tool for Accurate Determination of Albumin Glycation

We present the first demonstration of glycated albumin detection and quantification using Raman spectroscopy without the addition of reagents. Glycated albumin is an important marker for monitoring the long-term glycemic history of diabetics, especially as its concentrations, in contrast to glycated hemoglobin levels, are unaffected by changes in erythrocyte life times. Clinically, glycated albumin concentrations show a strong correlation with the development of serious diabetes complications including nephropathy and retinopathy. In this article, we propose and evaluate the efficacy of Raman spectroscopy for determination of this important analyte. By utilizing the pre-concentration obtained through drop-coating deposition, we show that glycation of albumin leads to subtle, but consistent, changes in vibrational features, which with the help of multivariate classification techniques can be used to discriminate glycated albumin from the unglycated variant with 100% accuracy. Moreover, we demonstrate that the calibration model developed on the glycated albumin spectral dataset shows high predictive power, even at substantially lower concentrations than those typically encountered in clinical practice. In fact, the limit of detection for glycated albumin measurements is calculated to be approximately four times lower than its minimum physiological concentration. Importantly, in relation to the existing detection methods for glycated albumin, the proposed method is also completely reagent-free, requires barely any sample preparation and has the potential for simultaneous determination of glycated hemoglobin levels as well. Given these key advantages, we believe that the proposed approach can provide a uniquely powerful tool for quantification of glycation status of proteins in biopharmaceutical development as well as for glycemic marker determination in routine clinical diagnostics in the future.National Center for Research Resources (U.S.) (Grant No. P41-RR02594)Massachusetts Institute of Technology. Laser Biomedical Research Cente

Spectroscopic approach for dynamic bioanalyte tracking with minimal concentration information

Vibrational spectroscopy has emerged as a promising tool for non-invasive, multiplexed measurement of blood constituents - an outstanding problem in biophotonics. Here, we propose a novel analytical framework that enables spectroscopy-based longitudinal tracking of chemical concentration without necessitating extensive a priori concentration information. The principal idea is to employ a concentration space transformation acquired from the spectral information, where these estimates are used together with the concentration profiles generated from the system kinetic model. Using blood glucose monitoring by Raman spectroscopy as an illustrative example, we demonstrate the efficacy of the proposed approach as compared to conventional calibration methods. Specifically, our approach exhibits a 35% reduction in error over partial least squares regression when applied to a dataset acquired from human subjects undergoing glucose tolerance tests. This method offers a new route at screening gestational diabetes and opens doors for continuous process monitoring without sample perturbation at intermediate time points.National Institute for Biomedical Imaging and Bioengineering (U.S.) (9P41EB015871-27)Kwansei Gakuin University (Grant 126004

Multi-color reflectance imaging of middle ear pathology in vivo

Otoscopic examination using white-light illumination has remained virtually unchanged for well over a century. However, the limited contrast of white-light otoscopy constrains the ability to make accurate assessment of middle ear pathology and is subject to significant observer variability. Here, we employ a modified otoscope with multi-color imaging capabilities for superior characterization of the middle ear constituents in vivo and for enhanced diagnosis of acute otitis media and cholesteatoma. In this pilot study, five patients undergoing surgery for tympanostomy tube placement and congenital cholesteatoma excision were imaged using the custom-designed multi-color video-rate reflectance imaging system. We show that the multi-color imaging approach offers an increase in image contrast, thereby enabling clear visualization of the middle ear constituents, especially of the tympanic membrane vascularity. Differential absorption at the multiple wavelengths provides a measure of biochemical and morphological information, and the rapid acquisition and analysis of these images aids in objective evaluation of the middle ear pathology. Our pilot study shows the potential of using label-free narrow-band reflectance imaging to differentiate middle ear pathological conditions from normal middle ear. This technique can aid in obtaining objective and reproducible diagnoses as well as provide assistance in guiding excisional procedures.Connecticut Institute for Clinical and Translational Science (CICATS)Johns Hopkins University. Whiting School of Engineering (Startup Funds

Label-free characterization of ultra violet-radiation-induced changes in skin fibroblasts with Raman spectroscopy and quantitative phase microscopy

Minimizing morbidities and mortalities associated with skin cancers requires sustained research with the goal of obtaining fresh insights into disease onset and progression under specific stimuli, particularly the influence of ultraviolet rays. In the present study, label-free profiling of skin fibroblasts exposed to time-bound ultra-violet radiation has been performed using quantitative phase imaging and Raman spectroscopy. Statistically significant differences in quantifiable biophysical parameters, such as matter density and cell dry mass, were observed with phase imaging. Accurate estimation of changes in the biochemical constituents, notably nucleic acids and proteins, was demonstrated through a combination of Raman spectroscopy and multivariate analysis of spectral patterns. Overall, the findings of this study demonstrate the promise of these non-perturbative optical modalities in accurately identifying cellular phenotypes and responses to external stimuli by combining molecular and biophysical information.National Institutes of Health (U.S.) (Grant P41-EB015871-30)National Institutes of Health (U.S.) (Grant U01-NS090438-03)National Institutes of Health (U.S.) (Grant R21-NS091982-01)National Institutes of Health (U.S.) (Grant R01-HL121386-03

Noninvasive morpho-molecular imaging reveals early therapy-induced senescence in human cancer cells

Anticancer therapy screening in vitro identifies additional treatments and improves clinical outcomes. Systematically, although most tested cells respond to cues with apoptosis, an appreciable portion enters a senescent state, a critical condition potentially driving tumor resistance and relapse. Conventional screening protocols would strongly benefit from prompt identification and monitoring of therapy-induced senescent (TIS) cells in their native form. We combined complementary all-optical, label-free, and quantitative microscopy techniques, based on coherent Raman scattering, multiphoton absorption, and interferometry, to explore the early onset and progression of this phenotype, which has been understudied in unperturbed conditions. We identified TIS manifestations as early as 24 hours following treatment, consisting of substantial mitochondrial rearrangement and increase of volume and dry mass, followed by accumulation of lipid vesicles starting at 72 hours. This work holds the potential to affect anticancer treatment research, by offering a label-free, rapid, and accurate method to identify initial TIS in tumor cells

Portable Optical Fiber Probe-Based Spectroscopic Scanner for Rapid Cancer Diagnosis: A New Tool for Intraoperative Margin Assessment

There continues to be a significant clinical need for rapid and reliable intraoperative margin assessment during cancer surgery. Here we describe a portable, quantitative, optical fiber probe-based, spectroscopic tissue scanner designed for intraoperative diagnostic imaging of surgical margins, which we tested in a proof of concept study in human tissue for breast cancer diagnosis. The tissue scanner combines both diffuse reflectance spectroscopy (DRS) and intrinsic fluorescence spectroscopy (IFS), and has hyperspectral imaging capability, acquiring full DRS and IFS spectra for each scanned image pixel. Modeling of the DRS and IFS spectra yields quantitative parameters that reflect the metabolic, biochemical and morphological state of tissue, which are translated into disease diagnosis. The tissue scanner has high spatial resolution (0.25 mm) over a wide field of view (10 cm×10 cm), and both high spectral resolution (2 nm) and high spectral contrast, readily distinguishing tissues with widely varying optical properties (bone, skeletal muscle, fat and connective tissue). Tissue-simulating phantom experiments confirm that the tissue scanner can quantitatively measure spectral parameters, such as hemoglobin concentration, in a physiologically relevant range with a high degree of accuracy (<5% error). Finally, studies using human breast tissues showed that the tissue scanner can detect small foci of breast cancer in a background of normal breast tissue. This tissue scanner is simpler in design, images a larger field of view at higher resolution and provides a more physically meaningful tissue diagnosis than other spectroscopic imaging systems currently reported in literatures. We believe this spectroscopic tissue scanner can provide real-time, comprehensive diagnostic imaging of surgical margins in excised tissues, overcoming the sampling limitation in current histopathology margin assessment. As such it is a significant step in the development of a platform technology for intraoperative management of cancer, a clinical problem that has been inadequately addressed to date.Case Comprehensive Cancer Center. Tissue Procurement, Histology and Immunohistochemistry Core Facility (P30 CA43703)National Cancer Institute (U.S.) (R01-CA140288)National Cancer Institute (U.S.) (R01-CA97966)National Center for Research Resources (U.S.) (S10-RR031845)National Center for Research Resources (U.S.) (P41-RR02594