Noninvasive Monitoring of Blood Glucose with Raman Spectroscopy

Abstract

CONSPECTUS The successful development of a noninvasive blood glucose sensor that can operate reliably over sustained periods of time has been a much sought after but elusive goal in diabetes management. Since diabetes has no well-established cure, control of elevated glucose levels is critical for avoiding severe secondary health complications in multiple organs including the retina, kidney and vasculature. While fingerstick testing continues to be the mainstay of blood glucose detection, advances in electrochemical sensing-based minimally invasive approaches have opened the door for alternate methods that would considerably improve the quality of life for people with diabetes. In the quest for better sensing approaches, optical technologies have surfaced as attractive candidates as researchers have sought to exploit the endogenous contrast of glucose, notably its absorption, scattering, and polarization properties. Vibrational spectroscopy, especially spontaneous Raman scattering, has exhibited substantial promise due to its exquisite molecular specificity and minimal interference of water in the spectral profiles acquired from the blood-tissue matrix. Yet, it has hitherto been challenging to leverage the Raman scattering signatures of glucose for prediction in all but the most basic studies and under the least demanding conditions. In this Account, we discuss the newly developed array of methodologies that address the key challenges in measuring blood glucose accurately using Raman spectroscopy and unlock new prospects for translation to sustained noninvasive measurements in people with diabetes. Owing to the weak intensity of spontaneous Raman scattering, recent research has focused on enhancement of signals from the blood constituents by designing novel excitation-collection geometries and tissue modulation methods while our attempts have led to the incorporation of nonimaging optical elements. Additionally, invoking mass transfer modeling into chemometric algorithms has not only addressed the physiological lag between the actual blood glucose and the measured interstitial fluid glucose values but also offered a powerful tool for predictive measurements of hypoglycemia. This framework has recently been extended to provide longitudinal tracking of glucose concentration without necessitating extensive a priori concentration information. These findings are advanced by the results of recent glucose tolerance studies in human subjects, which also hint at the need for designing nonlinear calibration models that can account for subject-to-subject variations in skin heterogeneity and hematocrit levels. Together, the emerging evidence underscores the promise of a blood withdrawal-free optical platform—featuring a combination of high-throughput Raman spectroscopic instrumentation and data analysis of subtle variations in spectral expression—for diabetes screening in the clinic and, ultimately, for personalized monitoring.

Evaluation of accuracy dependence of Raman spectroscopic models on the ratio of calibration and validation points for non-invasive glucose sensing

“…Leave-one-out or K-fold cross-validation methods are employed to establish the accuracy of spectral models against the reference values. Our long-term efforts in realizing the goal of non-invasive Raman glucose sensing have been evaluated by clamping studies in animals and oral glucose tolerance test (OGTT) in humans [17,20,21]. Recently Shao et al has shown that by focusing laser directly in to the blood stream of mouse models, problem of strong background can be avoided to some extent [22].…”

“…Weber et al developed a tabletop confocal Raman system to collect signals from interstitial fluid and tested this set-up on a group of 35 patients[24]. Even though results of these studies have provided substantial evidence in support of RS for monitoring glucose level one of the major hindrances in successful translation of spectroscopic glucose sensors for routine clinical usage is the unavailability of appropriate exit criterion for analyzing the unknown samples [21]. Efforts have been made towards developing a universal calibration model.…”

“…Three different calibration strategies using 50%, 30% and 18% of the total data as a reference have been employed and prediction accuracies of spectroscopic models are evaluated. In contrast to earlier studies where the accuracy of spectroscopic models was mostly accessed by ‘leave-one-out cross-validation’, here we have employed an ‘independent test prediction’ approach to obtain a realistic prospective read-out [17,21,20]. Also, an accurate reference method based on serum glucose has been used for better correlation.…”

Utility of Raman spectroscopy in diabetes detection based on biomarker Raman bands and in antidiabetic efficacy studies of herbal extract Rotheca myricoides Hochst

“…Diabetes is an irreversible metabolic condition and is only managed using proper medication and diet. A prediabetic condition is manifested through impaired fasting glucose and elevated levels of circulating branched‐chain amino acids (BCAA) in blood . At this stage (i.e., prediabetic), appropriate interventions that include physical exercise, low or no sugar diet, among others, can prevent development of type II diabetes mellitus .…”

“…This spectroscopic technique is increasingly generating a lot of interest in diabetes detection with spectral bands associated with some biomolecules acting as biomarkers. Some of the biomolecules that have been demonstrated using Raman spectroscopy to have a great potential in the detection and monitoring of diabetes mellitus type II include blood glucose, haemoglobin, lipids in erythrocyte membranes, and branched chain amino acids . Its use (i.e., Raman spectroscopy) in comparative efficacy studies of antidiabetic medications, both conventional and traditional, has been reported elsewhere …”