Introduction Breath analysis is an emerging field in gas sensor technology [1] aiming for the next generation of hand-held and non-invasive medical diagnostic and monitoring devices [2]. Often unrecognized, however, remains reliable and standardized breath sampling, a prerequisite for meaningful breath analysis. Nowadays, breath analysis is carried out mostly offline, i.e. that breath is collected and stored in a container (e.g. Tedlar bags) before examination. However, this requires thorough handling to ensure sample authenticity, short storage times as compounds may be lost and clean vessels surfaces to avoid contamination. More attractive is online breath analysis where the sample is guided directly to the analytical detector and evaluated instantaneously. When done with compact gas sensors (e.g. Si-doped WO3 for acetone [3]), this can result in portable breath analyzers [4, 5] being particularly attractive for personalized and routine monitoring of health parameters.Here, a simple sampler for controlled, monitored and reproducible end-tidal breath extraction is presented [6]. Due to its modular design, it is ideal for research purposes as it can be connected flexibly to various gas sensor types and even other analytical technologies (e.g. mass spectrometers) in contrast to previous sampler designs [4]. Furthermore, it enables simultaneous cross-validation with a bench-top analytical instrument. This sampler is characterized in detail on various major breath-relevant tracers (isoprene, ethanol and methanol) by state-of-the-art proton-transfer-reaction time-of-flight mass spectrometer (PTR-TOF-MS), after being already successfully tested with acetone on 20 subjects [3]. Methods Figure 1a shows a schematic cross-section of the sampler that comprises as inlet a disposable mouthpiece with droplet trap (EnviTeC-Wismar GmbH), a removable flow limiter orifice and an open-ended buffer tube. The custom-made orifice (green-colored, Figure 1b) features an inner diameter of 1.4 and a length of 12 mm. Relative airway pressure (pmouth – psurrounding) is monitored at the orifice using a differential pressure sensor (SDP2108, Sensirion). The orifice is initially calibrated by measuring the pressure drop at various flows of synthetic air (1.5 to 3 L min-1) provided by a gas mixing system described elsewhere [7]. A sampler tube length of 375 mm was applied, unless stated differently. The inner diameter was 25 mm. A transfer line connected to the sampling tube continuously extracts exhaled breath from the tube and draws the sample to the analysis unit consisting of a CO2 sensor (Capnostat 5, Respironics), an acetone gas sensor [3] and a PTR-TOF-MS. All surfaces in contact with breath (including transfer lines) as well as the sampling tube are either disposable (mouthpiece) or made of inert Teflon and heated to 65°C. Furthermore, the tube is jacketed with a thermally insulating layer of foamed silicone rubber. Results and Conclusions The sampler prompts subjects to exhale in a controlled and reproducible manner. Breath is exhaled through a disposable mouthpiece to avoid inter-subject cross-contamination (Figure 1a). Controlled exhalation flow is ensured with an orifice (green-colored, Figure 1b) at the sampler inlet creating a backpressure proportional to the exhalation flow rate. During exhalation, subjects are asked to maintain a constant airway pressure, and thus exhalation flow, guided by visual prompting. Typically, a pressure drop of 980 Pa across the orifice is targeted to maintain an exhalation flow rate of 50 mL s-1, as recommended for standardized sampling of exhaled NO [8]. After the orifice, breath enters the open-ended sampling tube and is pushed out until the last breath portion, i.e. the end-tidal fraction for a complete exhalation, remains and is buffered for analysis. Breath sample is extracted continuously from the tube front to a CO2 sensor to identify and monitor the breath portion and a gas sensor and/or PTR-TOF-MS for analyte quantification.As a first step, the sampler was characterized by PTR-TOF-MS with a simulated breath mixture (Figure 1c) containing breath-average concentrations of acetone (red line), ethanol (blue line), methanol (green line), isoprene (orange line) and CO2 (black line) in synthetic air at 90 % RH. Most importantly, when exposing the sampler to this mixture, the nominal analyte concentrations (dashed lines) are reached within 10 s.Finally, the sampler was applied to analyze exhalations of two healthy volunteers (# 1 and 2) online with a solid-state gas sensor based on Si-doped WO3 nanoparticles. As shown in Figure 2 (black line), the sensor rapidly responds to each exhalation and approaches steady state with reproducible responses of 1.75 (first three pulses) and 5.8 (last three pulses) during the buffered exposure to end-tidal breath. That way, the sensor correctly identifies the two different acetone concentrations corresponding to 700 and 2300 ppb, respectively, as measured by PTR-TOF-MS (blue line) and consistent with similar measurements [3, 9] .As a result, this sampler promotes reliable breath analysis with gas sensors in research and clinical settings. Furthermore, the proposed modular design can be flexibly combined with various types of other gas sensors and applied for sampling of different breath markers (including isoprene, ethanol and methanol).
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Mar 27, 2024
Shen-Hui Cai + 4
Open Access