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THE 8 INTERNATIONAL SYMPOSIUM ON ADVANCED TOPICS IN ELECTRICAL ENGINEERING May 23-25, 2013 Bucharest, Romania
NOESIS: A Nitric Oxide Exhaled Sensor Integrated System E. Zampetti, A. Bearzotti, A. Macagnano National Research Council - Institute for Microelectronics and Microsystems, Rome, Italy
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[email protected] Abstract- This work describes the results of a handheld sensor system for monitoring exhaled nitric oxide. The device was developed during a framework of 3-year national project “NOESIS” in cooperation with an Italian SME (Medical International Research S.r.l.). In this apparatus a conductive sensor based on titania nanofibers coated with an ultra-thin film of PEDOT:PSS is capable of detecting up to 5 ppb of NO gas. The sensor system implements a smart recirculation measurement methodology to comply recommendations of the American Thoracic Society and European Respiratory Society about the medical instrumentations devoted to monitor and diagnose the respiratory inflammations. Such implemented system executes the measure in 90 seconds, with an exhalation time of about 10 seconds..
national project “NOESIS”, FILAS Lazio, Call DTB 2009– 2011) for monitoring exhaled nitric oxide are described. The core of the device is based on a conductive sensor made of titania nanofibres coated by dipping with an ultra-thin layer of PEDOT:PSS. Such a sensor is held in a measurement chamber of PTFE and it is capable of detecting up to 5 ppb of nitrogen monoxide.
Keywords: Biomedical Device, Asthma, Nitric Oxide, Titania nanofibers, Electrospinning
I.
INTRODUCTION
The human breath analysis is becoming ever more a routinely noninvasive diagnostic test, though known since the time of ancient physician Hippocrates, for getting information about the clinical state of an individual. However, measuring and recognizing these disease markers, as nitric oxide for asthma inflammation [1, 2], has been a noteworthy problem due to the very low concentrations (ppb) of analyte molecules, as well as non-standardized protocols for breath sampling, the complex physiological parameters and the presence of exogenous gases and volatile organic compounds penetrating the body as a result of environmental exposure. The analytical instruments as mass and laser spectrometry and Fourier transform infrared spectroscopy have been the mainly tools involved into breath investigation so far [3, 4]. More recently, nanomaterial based sensors [5-7], for their unique features depending on their large surface to volume ratio and finite or quantum size effects, have been the focus of attention from both scientists and industrialists. Indeed in addition of the nanosensing devices potentiality of detecting analytes at molecular levels, they show substantial outcome in the equipment market especially in miniaturized sensing instruments: compact design, light weight, and portability. Consequently, nanostructured chemical sensors or chemical sensors array devices for diagnosing more complex pathologies like cancer have been designed and manufactured, thus improving the commercial prospects into diagnostics. In this work the performances of a handheld sensor system (in cooperation with Medical International Research S.r.l. in the framework of 3-year
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Fig. 1. NOESIS prototype, front size. The overall dimension is: 165 mm x 80 mm, with a thickness of about 40 mm. The device embedded pumps, valves, Nafion® tubing, an oxidizing cartridge, sensor chamber, electronic interface circuits and batteries.
In order to comply recommendations of the American Thoracic Society (ATS) and European Respiratory Society (ERS) about the medical instrumentations devoted to monitor and diagnose the respiratory inflammations, a smart recirculating measurement methodology has been implemented. The device must be able to detect nitric oxide, in the range 5 - 300 ppb, with a resolution at least of 5 ppb. Moreover the exhalation time should be close to 10 seconds. The developed prototype (Fig. 1) executes the measure in 90 seconds, with an exhalation time of 10 seconds, assuring the required resolution. II.
EXPERIMENTAL
Recently, as reported in a previous study [8], a chemo-sensor (Fig. 2) having a nanofibrous scaffold of titania, coated with an ultrathin film of poly3,4ethylenedioxythiophene:polystyrenesulfonate (PEDOT:PSS) was capable of revealing up to 5 ppb of NO, upon oxidation (by means of a proper oxidizing cartridge), flowing the gas throughout the sensor for at least 90 s.
perform the PEDOT:PSS deposition. A basic scheme of electrospinning apparatus is presented in Fig. 3. The typical electrospinning set-up consists of three major components: a high-voltage power supply, a syringe with a metallic needle and a grounded rotating collector. This deposition process uses a high voltage potential to inject the charge of a certain polarity into a polymer solution (contained into the syringe), which is accelerated toward a rotating collector (usually connected to ground). When the electrostatic attraction forces (between the liquid and collector) and the electrostatic repulsions (between like charges in the liquid) become stronger, the leading edge of the solution changes from a rounded to a cone. A polymer jet is ejected from the Taylor cone when the force due to the electric field exceeds the surface tension of the liquid. During the travel (through the atmosphere) the solvent evaporates and consequently polymer jet solidifies in fiber form (with nanoscale dimensions). Finally, nanofibres are collected on the substrate fixed on the rotating collector.
Fig. 3. Basic scheme of electrospinning apparatus. The syringe needle was connected to high DC potential (+V). The metallic collector can rotate up to 10000 rpm, in order to increase the nanofibers collection. A suitable electronic syringe pump controller regulated the polymer flux.
Fig. 2. Details of developed conductive sensor. The sensor transducer was an interdigitated electrodes structure made of platinum/titanium. The sensor overall dimensions were 5 mm x 5mm x 0.4 mm. The mean of titania nanofibers was about 60 nm. The PEDOT:PSS layer covered the scaffold with an homogenous conductive film 200 nm tick.
Electrospinning technique was used to fabricate the titania nanofibrous layer [9] and a dipping equipment was used to
Here the electrodes, held onto a grounded rotating collector, was covered by a thin layer of an electrospun nanofibrous layer and then placed into an oven for annealing under oxygen atmosphere, using a thermal ramp from room temperature up to 550 ◦C (1 ◦C min−1). A 5 h dwell time was applied in order to remove the polyvinylpyrrolidone (PVP), the carrier polymer, and achieve the crystallization of titania. The prototype of NOESIS, see Fig. 1, embedded pumps, valves, Nafion® tubing, an oxidizing cartridge, a sensor chamber, electronic interface circuits and batteries. In order to enhance the system performances a 24 bit digital converter was used together with a suitable conditioning circuit implemented with a very low noise OP-AMP (by Texas Instruments). This circuit interface allowed to set an ultrastable sensor operating voltage that was in the range of 0.1 –
0.5 V. Then a trans-impedance circuit transformed the sensor current variations in voltage shifts. Finally the A/D converted this signal to digital data. The sensor, a chemoresistor based on a interdigitated electrode of Pt-Ti with a suitable layout and coated with a highly sensitive nanocomposite layer, was housed in a measurement chamber having less than 0.5 cc volume. To make the sensor system suitable for NO breath monitoring, both the measuring procedures and the sensor sensitivity must comply the recommendation of the American Thoracic Society (ATS)/European Respiratory Society (ERS) [10]. In order to satisfy this requirement, a smart recirculation measuring methodology was implemented as well described in [11]. By this strategy, the previously stored gas flowing into the tubes after exhalation, could recirculate over the sensor until reaching a satisfactory response determined by the dynamic equilibrium among gas and interacting nanomaterial. The whole system was checked in laboratory and the proper functioning was also validated with commercial sensors of both NO (NO-A1, Alphasense) and NO2 (TGS2106, Figaro) using certified gases (Praxair, SIAD). III.
RESULTS AND DISCUSSION
The recirculation path (Fig. 4), lasting for 90s, confirmed an increase in three times at least of sensor response, when compared to a measurement of ten-seconds (the maximum time allowed to exhale recommended by ATS/ERS).
Fig. 5. Sensor response variations to a set of 18 measurements of nitric oxide concentrations in a range from 5 ppb to 100 ppb (top graph). In particular different cycles of NO measurements are represented (middle and bottom graph). Each measurement cycle was performed setting 90 s of recirculation time and 600 s of cleaning consisting of a flux of fresh air.
Fig. 4. Screen capture of NOESIS control panel useful to perform system calibration. In particular, the picture highlights the scheme of implemented recirculation system.
Initially the sensor performances were investigated at different concentrations of NO, using a system of delivering gas based on mass flow controllers.
This system was able to get different concentrations of NO in a carrier of air coming from a certified cylinder. Figure 5 depicts an example of measurements at 5 and 20 ppb from the bottom upwards, respectively. Each measurement cycle was performed setting 90 s of recirculation and 600 s of cleaning consisting of a flux of fresh air. The system output voltage depends on interface circuit parameter such as: bias voltage of the sensor, sensor conductance and trans-impedance circuit gain. These parameters can be set and optimized during the equipment calibration process. At the top of figure 5, the results of a linear regression model applied to the angular coefficient of the sensor responses are reported, for predicting the concentration of nitric oxide. Root mean square error (RMSE) has been calculated both for the entire range of concentrations from 0 to 100 ppb and for two sub-ranges.
Thereafter the NO concentration in the exhaled breath of a group of healthy volunteers was measured with a commercial diagnostic tool (NOBreath, Bedfont Scientific Ltd.) in order to use them as “blank” and for comparison with the prototype results. Therefore, during their exhalation phases, known concentrations of NO were added (by a 3-way valve) for testing the working of the device under conditions similar to those clinics (Fig. 6). When the sensor was exposed to NO concentrations between 5 ppb and 300 ppb (limited to 90s of measurements), sensor responses resulted to be linear and noticeably separate from the noise (Fig. 7), with an accuracy
