Human Breath Analysis Research Articles

Sample Preparation of Volatile Organic Compounds with Needle−Type Extraction Device

Needle−type extraction devices have been developed for the simple andsensitive determination of gaseous volatile organic compounds (VOCs) in gas chromatography (GC). The needle−type extraction device allows direct insertionoftheextraction medium into the GC injection port, therefore, simple and rapid desorption of the extracted analytes could be achieved. For simultaneous derivatization and preconcentration of VOCs, fiber−packed needle was developed. The fiber−packed needle was prepared with a bundle of fine filaments typically coated with methyl−polysiloxane. During the extraction, target analytes, such as volatile aldehydes or ethylene oxide, were simultaneously derivatized and concentrated in the extraction needle.Particle−packed needle has been developed for the extraction of VOCs commonly found in environmental gaseous samples. Several particulate materials, such as porous polymer particles or activated carbon, were employed as the extraction media for the respective target analytes. The particle−packed extraction needle was successfully appliedforvarious analytical situations, such as in−door air analysis, fire investigation and human breath analysis.

Applications of a confined DART (direct analysis in real time) ion source for online in vivo analysis of human breath

Human breath is composed of many volatile metabolites that can potentially provide information about a person's health status. A sensitive assay to identify these volatile organic compounds as biomarkers is ideal and important for early detection of many diseases. However, the diagnosis through online breath analysis based on mass spectrometry is difficult due to the low concentration of pertinent compounds in breath. The DART (direct analysis in real time) ion source is a novel atmospheric pressure ionization technique, which can efficiently ionize gaseous, liquid and solid samples with high throughput. A major problem in analysis of gaseous samples is its poor detection sensitivity due to open-air sampling. Recently, a confined DART ion source (cDART) was developed, where the plasma generated by the atmospheric pressure glow discharge ionizes gas-phase molecules in a Tee-shaped flow tube instead of open air. It leads to a significant increase of the ionization efficiency of gaseous samples. In this study, the cDART source was modified and applied in online analysis of exhaled breath. The limit of detection of the improved cDART source was determined to be at the level of low ppb. The cDART source was used in the real-time monitoring of an oral anesthetic drug. The concentration variations of two active ingredients in exhaled breath, menthol and benzocaine, and their metabolites with time were obtained. The results show that the cDART ion source is a powerful analytical tool to provide high sensitivity and high throughput analysis for volatile organic compounds in human breath, and can find potential applications in clinical diagnosis and therapy.

Low cost acetone sensors with selectivity over water vapor based on screen printed TiO2 nanoparticles

Noninvasive breath acetone sensors, in particular metal oxide based chemo-resistive sensors, have been actively researched recently for daily diabetes diagnosis. To find a safer alternative to the flame spray pyrolysis processing method, screen printing of commercial TiO2 paste is employed in the fabrication of metal oxide semiconductor chemo-resistors, without involving open flame, high temperature and costly instruments. The TiO2 sensing layer is found to have a desirable porous structure, with a specific surface area of 72.7 m2 g−1, when investigated using scanning electron microscopy and the Brunauer–Emmett–Teller isotherm. The new sensors are able to detect 1.5 ppm acetone, and are sensitive enough for type I diabetes diagnosis. The sensitivity survives in the presence of 90% relative humidity, offering a long targeted selectivity yet to be achieved, but essential for human breath analysis.

Monitoring Diurnal Changes in Exhaled Human Breath

The development of noninvasive analytical techniques is of interest to the field of chronobiology, in order to reveal the human metabolome that seems to show temporal patterns and to predict internal body time. We report on the real-time mass spectrometric analysis of human breath as a potential method to be used in this field. The breath of 12 subjects was analyzed during 9 days by secondary electrospray ionization-mass spectrometry (SESI-MS). The samples were collected during four time slots: morning (8:00-11:00), before lunch (11:00-13:00), after lunch (13:00-15:00), and late afternoon (15:00-18:00). A total of 203 mass spectra were statistically analyzed. Univariate analysis revealed a number of features with a marked temporal behavior. Principal component analysis/canonical analysis showed a clear temporal evolution of the breath patterns. A blind cross-validation yielded 84% of correct classifications of the time slot at which the breath samples were collected. We conclude that this approach seems to have potential for the investigation of biological clocks, including the description of internal body time, which may have important implications for the timing of pharmacotherapy.

A Workflow For The Metabolomic/Metabonomic Investigation of Exhaled Breath Using Thermal Desorption Gc–Ms

Confounding factors in the analysis of human breath by thermal desorption GC-MS are reviewed, with special emphasis on the high water levels encountered in human breath samples. Multilinear regression optimization of breath sampling factors, along with the selection of ubiquitous sample components used as retention-time standards, enabled data registration based on retention indexing and mass spectral alignment. This was done on a component-by-component basis. The methodology developed reconciled participant safety, artefacts from accelerated hydrolysis of the stationary phase and the destructive nature of thermal desorption. Furthermore, using ubiquitous methylated cyclic-siloxanes in the thermal desorption-GC-MS chromatograms enabled secondary retention indexing for each chromatogram. This methodology enables the creation of a 'breath matrix' that is based on a combination of retention indexing and the mass spectral registration of isolated peaks. This approach facilitated more efficient data modeling and a case study from a 22-participant (10 male, 12 female) stress-intervention experiment. Principal component analysis of data registered by retention indexing did not classify successfully stressed from unstressed states. By contrast, adoption of a breath matrix approach enabled 95% separation.

A comparison of spectroscopic techniques for human breath analysis

The analysis of human breath has been driven to new heights and has great potential to impact our society in the area of medical science. Breath analysis is promising as non-invasive, simple and point-of-care clinical measurements to reduce the medical burden caused by invasive, time-consuming and expensive clinical devices. Spectroscopic techniques for breath analysis can offer information to correlate its signals to exhaled substances for molecular identification and quantification to provide the pathophysiological status of the body. In this review paper, techniques such as mass spectrometry-based (gas chromatography-mass spectrometry, proton transfer reaction-mass spectrometry, selected ion flow tube-mass spectrometry), laser absorption spectroscopy-based (cavity ring down spectroscopy and tunable diode laser absorption spectroscopy) and other spectroscopic techniques for breath analysis applications are compared in terms of its advantages/disadvantages, versatilities and plausibility to be transformed in clinical applications.

Ultrasensitive laser spectroscopy for breath analysis

AbstractAt present there are many reasons for seeking new methods and technologies that aim to develop new and more perfect sensors for different chemical compounds. However, the main reasons are safety ensuring and health care. In the paper, recent advances in the human breath analysis by the use of different techniques are presented. We have selected non-invasive ones ensuring detection of pathogenic changes at a molecular level. The presence of certain molecules in the human breath is used as an indicator of a specific disease. Thus, the analysis of the human breath is very useful for health monitoring. We have shown some examples of diseases’ biomarkers and various methods capable of detecting them. Described methods have been divided into non-optical and optical methods. The former ones are the following: gas chromatography, flame ionization detection, mass spectrometry, ion mobility spectrometry, proton transfer reaction mass spectrometry, selected ion flow tube mass spectrometry. In recent twenty years, the optical methods have become more popular, especially the laser techniques. They have a great potential for detection and monitoring of the components in the gas phase. These methods are characterized by high sensitivity and good selectivity. The spectroscopic sensors provide the opportunity to detect specific gases and to measure their concentration either in a sampling place or a remote one. Multipass spectroscopy, cavity ring-down spectroscopy, and photo-acoustic spectroscopy were characterised in the paper as well.

Statistical and bioinformatical methods to differentiate chronic obstructive pulmonary disease (COPD) including lung cancer from healthy control by breath analysis using ion mobility spectrometry

Human breath analysis is a powerful and especially a non-invasive technique for the monitoring and hopefully also for the diagnosis of respiratory diseases, including chronic obstructive pulmonary disease (COPD). The exhaled breath of 95 patients suffering COPD and of 35 healthy controls was investigated using an Ion Mobility Spectrometer (IMS) coupled to a Multi-Capillary Column (MCC) without any pre-separation or pre-enrichment. Starting with the results from a Mann–Whitney-Wilcoxon rank sum test to find analytes with the highest potential with respect to differentiation, box and whisker plots, metabolic maps and probability charts were introduced and compared. In addition, the sensitivity, specificity, positive and negative predictive values and the accuracy of the relation were also summarized. The findings were compared to the results of a principal component analysis. Finally, decision trees were introduced to visualize the interdependencies between the analytes and the classifications. The application of these biostatistical methods with simultaneous inclusion of several VOCs for disease classification by ion mobility spectrometry of human breath will provide much more information than using single peaks and single concentration dependencies for disease classification and discrimination of various groups. Towards the future application of potential biomarkers for clinical diagnostic procedures, complex analytical methods, such as ion mobility spectrometry, need statistical and bioinformatical tools which are simple in application, visualize the results and support decisions on the basis of the data obtained from measurements of analytes in exhaled human breath.

Gas sensor using noble metal-loaded TiO2 nanotubes for detection of large-sized volatile organic compounds

Detection of volatile organic compounds (VOCs) has attracted considerable attention for indoor air quality and human breath analysis. Here, resistive-type gas sensors with porous films made of Au-loaded TiO2 nanotubes were developed for the detection of large-sized VOCs. Well-dispersed Au nanoparticles (10 to 20 nm) were photo-chemically deposited on TiO2 nanotubes (80 nm in diameter, 700 nm in length) prepared by a hydrothermal method. The device using the Au-loaded TiO2 nanotubes showed improved sensor responses to ethanol and toluene (50 ppm) in air at 500°C. This suggested that Au nanoparticles deposited on the surface of TiO2 nanotubules without aggregation. We also demonstrated that the device could be used for the detection of large-sized VOC molecule, i.e., 2,6-diisopropylphenol (propofol), an intravenously administered hypnotic drug for induction and maintenance of anesthesia. The Au-loaded TiO2 nanotubes would offer a way to continuously monitor a change in the concentration of VOCs in exhaled air for medical diagnostics.

Breath biomarkers for personalized medicine.

Personalized medicine, in the near future, has the potential to revolutionize healthcare by allowing physicians to individualize therapy for patients through the early diagnosis of disease and risk assessment to optimize clinical response with minimal toxicity. The identification of biomarkers could detect, diagnose and help guide therapy to improve survival and quality of life by the early identification of responders to the drugs. Volatile organic compounds and stable isotope-labeled 13CO2 in breath can be uniquely utilized as in vivo diagnostic biomarkers of disease and/or lack of enzyme activity to aid physicians to personalize medication. Noninvasive detection of ailments and monitoring therapy by human breath analysis is an emerging field of medical diagnostics representing a rapid, economic and simple alternative to standard invasive blood analysis, endoscopy or harmful imaging techniques such as x-ray and CT scans.

Si:WO3 Sensors for Highly Selective Detection of Acetone for Easy Diagnosis of Diabetes by Breath Analysis

Acetone in the human breath is an important marker for noninvasive diagnosis of diabetes. Here, novel chemo-resistive detectors have been developed that allow rapid measurement of ultralow acetone concentrations (down to 20 ppb) with high signal-to-noise ratio in ideal (dry air) and realistic (up to 90% RH) conditions. The detector films consist of (highly sensitive) pure and Si-doped WO(3) nanoparticles (10-13 nm in diameter) made in the gas phase and directly deposited onto interdigitated electrodes. Their sensing properties (selectivity, limit of detection, response, and recovery times) have been investigated as a function of operating temperature (325-500 degrees C), relative humidity (RH), and interfering analyte (ethanol or water vapor) concentration. It was found that Si-doping increases and stabilizes the acetone-selective epsilon-WO(3) phase while increasing its thermal stability and, thus, results in superior sensing performance with an optimum at about 10 mol % Si content. Furthermore, increasing the operation temperature decreased the detector response to water vapor, and above 400 degrees C, it was (<or=0.7) always below the threshold (10.6) for fake diabetes detection in ideal conditions. At this temperature and at 90% RH, healthy humans (<or=900 ppb acetone) and diabetes patients (>or=1800 ppb) can be clearly distinguished by a remarkable gap (40%) in sensor response. As a result, these solid state detectors may offer a portable and cost-effective alternative to more bulky systems for noninvasive diabetes detection by human breath analysis.

Analysis of Volatile and Non-Volatile Biomarkers in Human Breath Using Differential Mobility Spectrometry (DMS)

Exhaled human breath contains thousands of chemicals that are potential biomarkers of disease or chemical exposure. Although many bench-top analytical instruments could measure concentrations of these chemicals, small and portable systems have the best advantage of being used in a clinical point-of-care environment or in a field setting. Here, we demonstrate coupling a miniature differential mobility spectrometer (DMS) with both a gas chromatograph (GC) and separately an electrospray ionization (ESI) module to analyze exhaled breath condensate. Our combined GC/DMS and ESI/DMS instrument systems are capable of measuring an extremely large number of chemical analytes contained in exhaled breath condensate. We have established methodologies for detecting single compounds and approximate the limits of detection for our systems. The detection limit and analytical power are clinically relevant for many potential biomarkers, and suggests our device may have many applications for disease diagnostics in human breath analysis.

Human breath analysis: methods for sample collection and reduction of localized background effects

Solid-phase microextraction (SPME) was applied, in conjunction with gas chromatography-mass spectrometry, to the analysis of volatile organic compounds (VOCs) in human breath samples without requiring exhaled breath condensate collection. A new procedure, exhaled breath vapor (EBV) collection, involving the active sampling and preconcentration of a breath sample with a SPME fiber fitted inside a modified commercial breath-collection device, the RTube, is described. Immediately after sample collection, compounds are desorbed from the SPME fiber at 250 degrees C in the GC-MS injector. Experiments were performed using EBV collected at -80 degrees C and at room temperature, and the results compared to the traditional method of collecting exhaled breath condensate at -80 degrees C followed by passive SPME sampling of the collected condensate. Methods are compared in terms of portability, ease-of-use, speed of analysis, and detection limits. The need for a clean air supply for the study subjects is demonstrated using several localized sources of VOC contaminants including nail polish, lemonade, and gasoline. Various simple methods to supply clean inhaled air to a subject are presented. Chemical exposures are used to demonstrate the importance of providing cleaned air (organic vapor respirator) or an external air source (tubing stretched to a separate room). These techniques allow for facile data interpretation by minimizing background contaminants. It is demonstrated herein that this active SPME breath-sampling device provides advantages in the forms of faster sample collection and data analysis, apparatus portability and avoidance of power or cooling requirements, and performance for sample collection in a contaminated environment.

Laser-based human breath analysis: D/H isotope ratio increase following heavy water intake

Following the ingestion of only 5.1 mL of D2O, a mid-infrared laser spectrometer determines the D/H isotope ratio increase in exhaled water vapor for the first time, to the best of our knowledge. This increase is still detectable several weeks after the heavy water intake. Collected breath samples are directly transferred into a high-temperature multipass cell operated at 373 K. No breath sample preparation is required. Aside from the capability to hinder unwanted condensation, measurements at elevated temperatures offer other advantages such as a lower temperature dependence of the delta value or the possibility to vary the intensity of absorption lines. We lay the foundation for many laser-based clinical applications. As an example, we measure a total body water weight of 55.2%+/-1.8% with respect to the total body weight, in agreement with the normal value of the male population.

Sensing performance of thermoelectric hydrogen sensor for breath hydrogen analysis

We studied the sensing performance of the thermoelectric hydrogen sensor (THS) aimed at application to the human breath hydrogen (H 2) analysis for the evaluation of colonic flora. The THS has unique gas sensing performance such as H 2 selectivity and immunity to humidity. We have designed a simple human breath analysis system with this sensor, gas pump and dehumidifier of silica gel. The humidity of the human breath gas was controlled to be as low as 20% RH at 25 °C through the gas-drying tube because the humidity in the human breath gas causes serious noise effect. The THS system was able to detect 4–103 ppm of H 2 in human breath sample which coexisted with various gases such as methane (CH 4) and carbon monoxide (CO).

Determination of Acetone in Human Breath by Lithium Ion Attachment Mass Spectrometry

Lithium (Li) ion attachment mass spectrometry (IAMS) is a highly sensitive method for detecting volatile organic compounds (VOCs) without fragmentation in real-time. We have therefore developed a novel IAMS system for direct determination of trace amounts of VOCs by modifying the sampling cone interface. This technique was successfully applied to in situ analysis of human breath. It was shown that the concentrations of acetone in 7 healthy subjects ranged from 0 (not detectable) to 28.5 ppbv (parts per billion by volume) after a 15-hour overnight fast. The detection limit (3σ) is 0.55 ppbv for acetone and the relative standard deviation (RSD) is less than 9.7%. These results demonstrate that the newly developed IAMS system provides simple, rapid, and sensitive measurements of trace amounts of acetone in human breath, and that the system is promising for early diagnosis of diabetes.

Direct Analysis of Fatty Acid Vapors in Breath by Electrospray Ionization and Atmospheric Pressure Ionization-Mass Spectrometry

Real time analysis of human breath is achieved in an atmospheric pressure ionization mass spectrometer (API-MS) by negatively charging exhaled vapors via contact with an electrospray cloud. The spectrum observed is dominated by a wide range of deprotonated fatty acids, including saturated chains up to C14. Above C14, the background from cutaneous sources becomes dominant. We also tentatively identify a series of unsaturated fatty acids (C7-C10), ketomonocarboxylic acids (C6-C10), and a family of aldehydes. The ionization probability of large fatty acids increases drastically when the humidity changes from 20% to 95%. Accordingly, distinguishing lung vapors (humid) from those in the background (dry) requires special precautions. Estimated fatty acid vapor concentrations in breath based on our measurements ( approximately 100 ppt) are in fair agreement with values expected from blood concentrations in the range for which data are available (C3-C6).

Ferroelectric WO3 Nanoparticles for Acetone Selective Detection

Ferroelectric ε-WO3 nanoparticles were synthesized and stabilized above room temperature for the first time. A sensor based on this material was found to be highly sensitive and selective to acetone gas which will serve as a good candidate for diabetes diagnosis based on human breath analysis.

Cavity-enhanced direct frequency comb spectroscopy

Cavity-enhanced direct frequency comb spectroscopy combines broad spectral bandwidth, high spectral resolution, precise frequency calibration, and ultrahigh detection sensitivity, all in one experimental platform based on an optical frequency comb interacting with a high-finesse optical cavity. Precise control of the optical frequency comb allows highly efficient, coherent coupling of individual comb components with corresponding resonant modes of the high-finesse cavity. The long cavity lifetime dramatically enhances the effective interaction between the light field and intracavity matter, increasing the sensitivity for measurement of optical losses by a factor that is on the order of the cavity finesse. The use of low-dispersion mirrors permits almost the entire spectral bandwidth of the frequency comb to be employed for detection, covering a range of ~10% of the actual optical frequency. The light transmitted from the cavity is spectrally resolved to provide a multitude of detection channels with spectral resolutions ranging from a several gigahertz to hundreds of kilohertz. In this review we will discuss the principle of cavity-enhanced direct frequency comb spectroscopy and the various implementations of such systems. In particular, we discuss several types of UV, optical, and IR frequency comb sources and optical cavity designs that can be used for specific spectroscopic applications. We present several cavity-comb coupling methods to take advantage of the broad spectral bandwidth and narrow spectral components of a frequency comb. Finally, we present a series of experimental measurements on trace gas detections, human breath analysis, and characterization of cold molecular beams.

A Breath Ammonia Sensor Based on Conducting Polymer Nanojunctions

We present an ammonia sensor for human breath analysis based on electrically conducting polymer nanojunctions. Each nanojunction is formed by bridging a pair of gold nanoelectrodes on a silicon chip separated by a small gap (<60 nm) with electrodeposited polyaniline. The signal transduction mechanism of the sensor is the change in the nanojunction conductance as a result of polymer dedoping by ammonia. The sensor response to human breath is validated by comparison with a reference method for detection of ammonium ion combined with an optimized breath ammonia trapping system. The nanojunction sensor is capable of in situ detection of parts per billion (ppb) levels of ammonia in human breath.