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This letter presents the first quantitative, in vivo, transcutaneous glucose measurements using surface enhanced Raman spectroscopy (SERS). Silver film over nanosphere (AgFON) surfaces were functionalized with a mixed self-assembled monolayer (SAM) and implanted subcutaneously in a Sprague-Dawley rat. The glucose concentration was monitored in the interstitial fluid. SER spectra were collected from the sensor chip through the skin using spatially offset Raman spectroscopy (SORS). The combination of SERS and SORS is a powerful new approach to the challenging problem of in vivo metabolite and drug sensing. 10.1021/ac101951j

Lactate production under anaerobic conditions is indicative of human performance levels, fatigue, and hydration. Elevated lactate levels result from several medical conditions including congestive heart failure, hypoxia, and diabetic ketoacidosis. Real-time detection of lactate can therefore be useful for monitoring these medical conditions, posttrauma situations, and in evaluating the physical condition of a person engaged in strenuous activity. This paper represents a proof-of-concept demonstration of a lactate sensor based on surface-enhanced Raman spectroscopy (SERS). Furthermore, it points the direction toward a multianalyte sensing platform. A mixed decanethiol/mercaptohexanol partition layer is used herein to demonstrate SERS lactate sensing. The reversibility of the sensor surface is characterized by exposing it alternately to aqueous lactate solutions and buffer without lactate. The partitioning and departitioning time constants were both found to be ~30 s. In addition, physiological lactate levels (i.e., 6-240 mg/dL) were quantified in phosphate-buffered saline medium using multivariate analysis with a root-mean-square error of prediction of 39.6 mg/dL. Finally, reversibility was tested for sequential glucose and lactate exposures. Complete partitioning and departitioning of both analytes was demonstrated.

This paper presents the first in vivo application of surface-enhanced Raman scattering (SERS). SERS was used to obtain quantitative in vivo glucose measurements from an animal model. Silver film over nanosphere surfaces were functionalized with a two-component self-assembled monolayer, and subcutaneously implanted in a Sprague--Dawley rat such that the glucose concentration of the interstitial fluid could be measured by spectroscopically addressing the sensor through an optical window. The sensor had relatively low error (RMSEC = 7.46 mg/dL (0.41 mM) and RMSEP = 53.42 mg/dL (2.97 mM).

A new, mixed decanethiol (DT)/mercaptohexanol (MH) partition layer with dramatically improved properties has been developed for glucose sensing by surface-enhanced Raman spectroscopy. This work represents significant progress toward our long-term goal of a minimally invasive, continuous, reusable glucose sensor. The DT/MH-functionalized surface has greater temporal stability, demonstrates rapid, reversible partitioning and departitioning, and is simpler to control compared to the tri(ethylene glycol) monolayer used previously. The data herein show that this DT/MH-functionalized surface is stable for at least 10 days in bovine plasma. Reversibility is demonstrated by exposing the sensor alternately to 0 and 100 mM aqueous glucose solutions (pH ~7). The difference spectra show that complete partitioning and departitioning occur. Furthermore, physiological levels of glucose in two complex media were quantified using multivariate analysis. In the first system, the sensor is exposed to a solution consisting of water with 1 mM lactate and 2.5 mM urea. The root-mean-squared error of prediction (RMSEP) is 92.17 mg/dL (5.12 mM) with 87% of the validation points falling within the A and B range of the Clarke error grid. In the second, more complex system, glucose is measured in the presence of bovine plasma. The RMSEP is 83.16 mg/dL (4.62 mM) with 85% of the validation points falling within the A and B range of the Clarke error grid. Finally, to evaluate the real-time response of the sensor, the 1/e time constant for glucose partitioning and departitioning in the bovine plasma environment was calculated. The time constant is 28 s for partitioning and 25 s for departitioning, indicating the rapid interaction between the SAM and glucose that is essential for continuous sensing.

This research presents the achievement of significant milestones toward the development of a minimally invasive, continuously monitoring, glucose-sensing platform based on the optical quantitation of glucose in interstitial fluid. We expand our initial successes in the measurement of glucose by surface-enhanced Raman scattering (SERS), demonstrating substantial improvements not only in the quality and optical properties of the substrate system itself but also in the robusmess of the measurement methodology and the amenability of the technique to compact, diode laser-based instrumentation. Herein, we compare the long-term stability of gold to silver film over nanosphere (AuFON, AgFON) substrates functionalized with a partitioning self-assembled monolayer (SAM) using both electrochemical and SERS measurements. AuFONs were found to be stable for a period of at least 11 days. The switch to AuFONs not only provides a more stable surface for SAM formation but also yields better chemometric results, with improved calibration and validation over a range of 0.5-44 mM (10-800 mg/dL). Measured values for glucose concentrations in phosphate-buffered saline (pH ~7.4) based on 160 independent SERS measurements on AuFONs have a root-mean-square error of prediction of 2.7 mM (49.5 mg/dL), with 91% of the values falling within an extended A-B range on an expanded Clarke error grid. Furthermore, AuFONs exhibit surface plasmon resonances at longer wavelengths than similar AgFONs, which make them more efficient for SERS at near-infrared wavelengths, enabling the use of low-power diode lasers in future devices.

Choroidal perfusion measurements are complicated by the choroid's location posterior to the retina and its associated retinal blood vessels. Optical coherence tomography is a relatively new imaging technique with sufficient spatial resolution to isolate choroidal backscattering events from the posterior eye. We modified a speckle imaging algorithm to analyze sequential axial depth scans obtained from posterior rat eye to obtain an indicator of choroidal perfusion. This indicator is correlated with known changes in choroidal blood flow in response to increased intraocular pressure. OCIS codes: 170.4500, 110.4500, 170.1650, 170.0110, 170.6480.

The initial steps toward a miniature, field portable sensor based on surface-enhanced Raman spectroscopy (SERS) are presented. It is demonstrated that a low-cost miniaturized Raman system can be used in place of a larger, higher-cost conventional Raman system. This system was developed by sequentially replacing components of a laboratory scale Raman spectroscopy system with smaller, lower-cost, commercially available components. For example, a green laser pointer was used as the excitation source, a reflectance probe fiber-optic cable was used for laser delivery and collection, and a compact card-based spectrometer was used for dispersion and detection. Spectra, collected with the laser pointer Raman system, are presented of a resonant (Rhodamine 6G) and a non-resonant (trans-1,2-bis(4-pyridyl)ethylene) molecule as well as a self-assembled monolayer (1-decanethiol). Small, low-cost sensors are in demand for a variety of applications, and SERS is positioned to contribute significantly with its remarkable sensitivity and molecular specificity. Key words: Raman, SERS, fiber-optics, sensor.

We report a new method by which phase slope and group dispersion can be calculated with a simple optical low-coherence reflectometer to quantify physiological conditions. A discrete-time signal processing algorithm based on the first and second derivatives of the phase with respect to wave number was developed from discrete-time Fourier properties. The algorithm avoids the 2[pi] ambiguity associated with most phase unwrapping. Experimental data collected by use of well-characterized optical materials validated the algorithm, which was minimally sensitive to phase noise. The group dispersion of bovine cornea was measured at various hydrations and was significantly dependent on hydration. The results suggest that group dispersion is an indicator of corneal alterations. OCIS codes: 070.6020, 260.2030, 120.5050, 120.3180, 170.4500.

The use of surface-enhanced Raman spectroscopy for a systematic detection of glucose is described. Glucose is preconcentrated within the zone of electromagnetic field enhancement for this purpose.

The effects of fluid shear stress on the synthesis of platelet-derived growth factors (PDGF) peptides and endothelin-1 (ET-1) were analyzed in rat visceral pleura mesothelial (RVPM) cells. Exposure of cultured RVPM to cyclic strain stimulated the release of ET-1 and activated the mitogenic activity of pleural mesothelial cells. However, exposure of RVPM to shear stress or cyclic strain did not alter the secretion of PDGF.

Both theoretical and experimental studies of pleural fluid dynamics and lung buoyancy during steady-state, apneic conditions are presented. The theory shows that steady-state, top-to-bottom pleural-liquid flow creates a pressure distribution that opposes lung buoyancy. These two forces may balance, permitting dynamic lung floating, but when they do not, pleural--pleural contact is required. The animal experiments examine pleural-liquid pressure distributions in response to simulated reduced gravity, achieved by lung inflation with perfluorocarbon liquid as compared to air. The resulting decrease in lung buoyancy modifies the force balance in the pleural fluid, which is reflected in its vertical pressure gradient. The data and model show that the decrease in buoyancy with perfluorocarbon inflation causes the vertical pressure gradient to approach hydrostatic. In the microgravity analogue, the pleural pressures would be toward a more uniform distribution, consistent with ventilation studies during space flight. The pleural liquid turnover predicted by the model is computed and found to be comparable to experimental values from the literature. The model provides the flow field, which can be used to develop a full transport theory for molecular and cellular constituents that are found in pleural fluid. [DOI: 10.1115/1.1392317]