J. Kottmann, J. Rey and M.W. Sigrist
The objective of the study is the development of an infrared laser-based photo-acoustic device, which is able to measure glucose concentration in vitro and in vivo at levels within the physiological range. This research should contribute towards the development of a non-invasive glucose sensor, which would circumvent the need of daily blood sample taking for diabetic patients.
For a PA signal generation a sample is irradiated with either amplitude-modulated or pulsed light . The molecules of interest present in the sample absorb radiation of a characteristic part of the spectrum and convert the incoming optical energy, into a periodic heating of the sample by means of non-radiative relaxation processes. This leads to a modulated volumetric expansion and to the propagation of a thermal and acoustic wave inside the sample. The acoustic wave can then be detected with a microphone within a PA cell placed on the sample surface or with a piezoelectric transducer in direct contact with the sample surface.
The MIR region (5-25 μm) of the spectrum is particularly attractive for studies of biological samples since most molecules have a characteristic absorption spectrum in this wavelength range. PA spectroscopy is especially interesting for biomedical studies since it is (i) non-invasive (for moderate laser intensities), (ii) much less influenced by scattering effects than alternative optical techniques, and (iii) readily adaptable to the study of biological tissues. The MIR region has the big advantage that the glucose spectrum does not interfere as much with other blood and tissue constituents as it does in the near infrared and it shows distinct absorption maxima. However water as the main constituent of the human body tissue absorbs very strongly in the MIR and leads to penetration depths of less than 100 µm depending on the measurement site. These two aspects make the detection of glucose challenging.
We implemented a PA setup for in vitro and in vivo measurements. It employs an external-cavity quantum-cascade laser (1010-1095 cm-1) as an excitation source. The PA cell is employed to investigate glucose in aqueous solutions, gels or skin samples. All these samples are characterized by a high water content. During the measurement evaporating water leads to varying conditions in the PA chamber (e.g., changing light absorption or relative humidity) and causes unstable signals. To circumvent variations in relative humidity and condensation the PA chamber is either sealed with a diamond-window  or constantly ventilated with N2 .
The current detection limit of glucose in aqueous solution is below 50 mg/dl (SNR=1, Fig. 1)  and below 100 mg/dl (SNR=1) in epidermal skin . Both detection limits lie within the physiological range (30-500 mg/dl) but further improvements are necessary to monitor non-invasively glucose levels of diabetes patients. In the epidermal skin samples the glucose concentration is altered via passive diffusion from a glucose solution in contact with the lower epidermal layers. The diffusion process could be studied successfully with PA measurements.
|Fig. 1 Dependence of the PA signal on glucose concentration measured in aqueous solution close to the absorption maximum of glucose at 1034 cm-1. The inset shows an FTIR spectrum of different glucose solutions (with subtracted water background) in the mid-infrared and the tuning range of the quantum-cascade laser.|
For In vivo measurements the PA cell is put directly on the skin surface (Figs 2 and 3). In addition to the laser-induced PA signal a periodic signal caused by blood pulsation (0.8-1.2 Hz) is observed.
|Fig. 2 Schematic of the PA setup used for in-vivo measurements.|
|Fig. 3 Picture of the PA cell attached to the forearm for in vivo investigation.|
In a next step we aim to track glucose variations in vivo at the human forearm induced by the uptake of a standardized glucose drink (i.e., perform an oral glucose tolerance test). Some reasonable correlations were found between the continuously measured PA signal and the actual blood glucose concentration measured invasively using a commercial device. Nevertheless the strong signal instabilities observed during these in vivo experiments still need to be addressed.
This study is financially supported by the GlucoMetrix NIB & Non Invasive Diagnostic GmbH and the ETH Zurich.
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