In vivo evaluation of a chip based near infrared sensor for continuous glucose monitoring
Introduction
Diabetes is an incurable disease which, in case that it is not controlled accurately, may result in long term health complications, such as heart disease, stroke, kidney failure, and nervous system disorders. One of the major challenges in successful management of diabetes is the accurate knowledge of the actual blood glucose concentration. The real time monitoring of glucose concentrations will allow the diabetic patient to compensate by diet, oral medication, or insulin injections. An early diagnosis and tight glycaemic control can greatly diminish the medical complications and cost of this disease. Moreover, continuous blood glucose sensors of high accuracy serve as the basis for automatic glucose control (AGC), where a sensor is combined with an appropriate control algorithm and an insulin pump for frequent insulin delivery (Chee and Fernando, 2007, Hovorka, 2006, Klonoff, 2005). A good overview on state of the art glucose sensor development is given in (Gifford, 2013). Usually these sensors face a number of problems influencing their accuracy, such as invasiveness, calibration of the sensor, selectivity of the sensor, sensor fouling or degradation of the sensor underlying enzymes or fluorophores (Vaddiraju et al., 2010). To overcome the invasiveness of several sensor principles, near infrared (NIR) diffuse reflectance spectroscopy was applied, measuring through the skin the backscattered light of an NIR light source (Arnold et al., 2009, Xu and Wang, 2009). However, this technique faces the problem of an undefined optical path length, as well as optical interference of the skin and other components present in the tissue, requiring multivariate calibration routines to get sufficient information on the glucose concentration (Burmeister et al., 2000, Marbach et al., 2009).
In this paper a minimally invasive, opto-fluidic near infrared (NIR) difference spectroscopy glucose sensor is introduced, that provides continuous, reagent-free, optical analysis of interstitial fluid (ISF) or blood, based on microdialysis. Microdialysis is a widely investigated method for in-vivo analyte collection via a semi-permeable membrane (Stenken, 2009). In the concept introduced here, the analyte (interstitial liquid or blood plasma) is separated from other organic compounds, such as cells, fat, and proteins by using a micro-dialysis body interface and the background signal is discriminated from the glucose signal by using difference absorption spectroscopy. The concept of difference absorption spectroscopy in the 1st overtone band (1540–1820 nm) or the combination band (2000–2500 nm) of the NIR spectrum is already known and described in literature (Meuer 2002). The molar absorptivity of glucose and other biological molecules in aqueous solutions has been covered in detail in a review (Amerov et al., 2004). In Particular the wavelength band of the 1st overtone band can easily be addressed by conventional LED's, allowing for integrated compact sensor systems that are wearable by patients. Such wearable sensors, composed of a microfluidic chamber combined with microdialysis and a broadband LED, covering the combination band region as well as a variable filter and a detector array, acting as a miniaturized spectrometer, have already been suggested in the past (Olesberg et al., 2006). However, operability was not demonstrated.
Based on in-vitro measurements on aqueous solutions, containing glucose of concentrations in the physiologically relevant range of 50–200 mg/dl, by applying difference transmission spectroscopy, it was found that sensitivity relative to glucose in the 1st overtone band is higher than in the combination band. It was therefore decided to set up a miniaturized sensor system based on LED technology in the 1st overtone band in combination with a disposable microfluidic chip connected to a microdialysis catheter and containing the optical cells for difference absorption spectroscopy.
Section snippets
Sensor fundamentals and concept
The sensor introduced here is based on NIR difference absorption spectroscopy. The sensor consists of a multi-emitter LED with three LED's on one chip emitting at 1300 nm, 1450 nm and 1550 nm at about 1 mW power per emitter. The LED's together with two InGaAs-photodiodes are located on a single electronic board (non-disposable part) which in a first step was connected to a personal computer via an RS232 interface (Fig. 1).
A disposable chip is situated on top of the electronic board. The chip
In-vitro measurements
Typical difference spectra of glucose dissolved in pure water have been performed with a laboratory spectrometer Perkin Elmer Lambda 900. Evidently the strongest intensity changes (area under the difference absorbance curve) appear in the wavelength range of 1400–1500 nm (Ben Mohammadi et al., 2012). A less prominent change of the difference spectrum occurs at around 1550 nm which, however, is difficult to be addressed with a broadband LED. Therefore, in a first step the range from 1400 to 1500 nm
Conclusions
A sensor for continuous glucose measurements, based on NIR difference spectroscopy in the 1st overtone region of the spectrum was introduced. The sensor was combined with intravascular microdialysis to separate the glucose from the cells and proteins in the blood and operates without any chemical consumption during operation. Therefore, the sensors life time is limited only by fouling of the microdialysis catheter. In-vitro measurements showed an error of lower than 10 mg/dl and a relative error
Acknowledgments
This work was supported by the European Union in the seventh framework program project REACTION (Grant agreement no.: FP7 248590). The Medical University of Graz thankfully acknowledged for support in performing the clinical studies.
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