Wearable Breath Gas Sensors for Chronic Disease Management: Challenges and Perspectives

Exhaled breath analysis has gained considerable interest as a noninvasive diagnostic tool capable of detecting volatile organic compounds (VOCs) and inorganic gases that serve as biomarkers for various diseases. Polymer-based gas sensors have garnered significant attention due to their high sensitivity, room-temperature operation, excellent flexibility, and tunable chemical properties. This review comprehensively summarized recent advancements in polymer-based gas sensors for the detection of disease biomarkers in exhaled breath. The gas-sensing mechanism of polymers, along with novel gas-sensitive materials such as conductive polymers, polymer composites, and functionalized polymers was examined in detail. Moreover, key applications in diagnosing diseases, including asthma, chronic kidney disease, lung cancer, and diabetes, were highlighted through detecting specific biomarkers. Furthermore, current challenges related to sensor selectivity, stability, and interference from environmental humidity were discussed, and potential solutions were proposed. Future perspectives were offered on the development of next-generation polymer-based sensors, including the integration of machine learning for data analysis and the design of electronic-nose (e-nose) sensor arrays.

In general, volatile organic compounds (VOCs) have a high vapor pressure at room temperature (RT). It has been reported that all humans generate unique VOC profiles in their exhaled breath which can be utilized as biomarkers to diagnose disease conditions. The VOCs available in exhaled human breath are the products of metabolic activity in the body and, therefore, any changes in its control level can be utilized to diagnose specific diseases. More than 1000 VOCs have been identified in exhaled human breath along with the respiratory droplets which provide rich information on overall health conditions. This provides great potential as a biomarker for a disease that can be sampled non-invasively from exhaled breath with breath biopsy. However, it is still a great challenge to develop a quick responsive, highly selective, and sensitive VOC-sensing system. The VOC sensors are usually coated with various sensing materials to achieve target-specific detection and real-time monitoring of the VOC molecules in the exhaled breath. These VOC-sensing materials have been the subject of huge interest and extensive research has been done in developing various sensing tools based on electrochemical, chemoresistive, and optical methods. The target-sensitive material with excellent sensing performance and capturing of the VOC molecules can be achieved by optimizing the materials, methods, and its thickness. This review paper extensively provides a detailed literature survey on various non-biological VOC-sensing materials including metal oxides, polymers, composites, and other novel materials. Furthermore, this review provides the associated limitations of each material and a summary table comparing the performance of various sensing materials to give a better insight to the readers.

Background Following creation of an IPAA in patients with ulcerative colitis (UC), more than 60% of subjects develop inflammatory complications. The current objective assessment for inflammation of the pouch is limited to surrogate stool and blood biomarkers or endoscopy. The development of non-invasive and accurate biomarkers for the assessment of IPAA inflammation is an area of unmet need. Measurement of exhaled breath volatile organic metabolome compounds (VOCs) has shown promise as a biomarker for the diagnosis and monitoring of inflammatory disorders. We here aimed to characterize the pattern of VOCs in the exhaled breath of patients with an IPAA and assess whether VOC analysis is able to discriminate patients with endoscopically active IPAA inflammation from patients without IPAA inflammation. Methods This is a cross-sectional study of patients with an IPAA created for the management of UC. Exhaled breath samples were collected at time of endoscopic evaluation of the pouch and 97 VOC metabolites assessed via selective ion flow tube mass spectrometry (SIFT-MS). The IPAA cohort was dichotomized using the endoscopic pouch disease activity index (PDAI) into endoscopic PDAI of >= 4 (severe inflammation), or endoscopic PDAI score <= 1 (mild or no inflammation). Principle component analysis (PCA) was conducted to reveal the VOCs with the strongest discriminatory capability and principle component regression (PCR) was performed to assess the association of exhaled breath VOC analysis in differentiating the groups. Results Exhaled breath metabolome analysis was performed on 10 subjects with PDAI >=4 and 7 subjects with PDAI <=1. Demographics are provided in Table 1. PCA indicated robust discrimination of the two groups based on breath VOCs (Figure 1). 10 out of 97 VOCs were up-regulated in the PDAI >=4 group compared to control, including ammonia and hydrogen sulfide. Isopropenyltoluene, tetrachloroethylene, and 3-pentanone provided the highest contribution to differentiate between the cohorts (Figure 2). Receiver operative curve (ROC) analysis of the PCR model indicated an area under the curve (AUC) of 0.81 (0.61-99), suggesting a strong association of breath VOCs with inflammation of the pouch (Figure 1). Conclusion VOC exhaled breath metabolome analysis shows a strong ability to discriminate patients with severe endoscopic pouch inflammation from patients with minimal to no endoscopic inflammation. The differences in reported VOCs point toward metabolic differences in bacterial fermentation, lipid and carbohydrate metabolism, and an increase in reactive oxygen species in patients with endoscopic pouch inflammation. Validation studies addressing the role of VOC analysis for non-invasive disease assessment patients with IPAA are ongoing.

There has been considerable effort to develop wearable electronics from life-supporting devices for solders to fashion accessories such as smartwatches. The research of gas sensors has also attempted to adapt wearables with the power of nanotechnology. On the wearable platform, miniature gas sensors will provide real-time information about the atmosphere to protect each personnel from possible hazardous chemical attacks. In addition, wearable gas sensors can be facilitated to monitor human’s breath as medical applications. [1] Continuous monitoring of respiratory rate in real-time can act as a crucial benchmark for non-invasively detecting cardiac or arterial vascular function. Anomalies in respiratory rate serve as a significant indicator of a patient's health deterioration. Furthermore, it has been reported that aberrations in respiratory rate, as a physiological parameter, can be utilized to monitor common COVID-19 symptoms [2]. The analysis of breath through identifying biomarkers in exhaled breath proves to be an effective method for assessing metabolic disorders or dysfunctions in the human body. Conducting polymers (CPs) have generated significant interest in constructing flexible gas sensors. The inherent issue with pure CPs lies in their tendency to deprotonate in the presence of air, leading to a notable decline in long-term stability. Furthermore, limited gas response on diverse gaseous species demands the exploration of hybridizing CPs and other nanomaterials. When nanomaterials are hybridized with CPs, a synergistic effect, which comes from the benefits of each material, can improve sensing performance.In this study, polyaniline (PANI) conducting polymer and carbon-based nanomaterials, including carbon nanotubes (CNTs), graphene, or MXene were synthesized in a composite form and deposited into disposable masks. The developed gas sensor demonstrates remarkable stability attributed to the presence of van der Waals forces and π–π interactions between carbon-based nanomaterials and polyaniline (PANI). This stability is crucial for its reliable performance over time. The sensor's sensitivity is notably improved due to enhanced charge transfer channels and a porous structure that facilitates the adsorption of target gas. Additionally, the composite sensors detect breathing patterns in real-time, which demonstrates noninvasive human breath monitoring. A noteworthy aspect is that a significant portion of breath signals originates from the presence of target gases and moisture in exhaled breath. Although volatile sulfur compounds, CO2, and volatile organic compounds in the exhaled breath have a minimal influence on the sensing signals, the sensor remains highly responsive to the key components, particularly target gas by selecting carbon-based nanomaterials [3, 4]. The proposed gas sensing mechanism of the CP-based composites is discussed.

First responders, such as law enforcement officers or emergency medical personnel, are often faced with making critical decisions for scene management before knowing the root cause of the incident. Unfortunately, the threat of chemical and biological terror acts remains a growing global concern and when such events occur the timing of chemical and biological information is critical. Therefore, it is imperative that advances be made in bringing rapid chemical analysis directly into the field.Wearable electrochemical sensors are well placed to fill this technology gap to advance real-time chemical analytics at the point-of-need. The seamless integration of chemical sensors and biosensors within wearable platforms brings the power of laboratory-based chemical analyses directly to the wearer’s body [1]. While the majority of these wearable sensor systems have focused on healthcare and fitness applications, there are growing demands for developing wearable sensor platforms for rapid and on-site chemical threat assessment for a diverse range of forensic, security and defence applications.To this effect, this presentation will detail recent progress in glove-based wearable electrochemical sensors, where electrochemical sensing modalities are coupled to dexterous and tactile sampling strategies to provide critical chemical information where needed the most [2]. In particular, there will be a focus on the integration of enzymatic biosensors for the detection of organophosphorus chemical threats [3], through to the development of an electrochemical assay for the synthetic opioid fentanyl [4] and subsequent translation to a glove-based wearable platform [5]. Challenges and future prospects for glove-based wearable electrochemical sensors will be discussed in relation to on-site chemical threat assessment applications.

Research on remote health monitoring through wearable sensors has attained popularity in recent decades mainly due to aging population and expensive health care services. Microfluidic wearable sweat sensors provide economical, non-invasive mode of sample collection, important physiological information, and continuous tracking of human health. Recent advances in wearable sensors focus on electrochemical monitoring of biomarkers in sweat and can be applicable in various fields like fitness monitoring, nutrition, and medical diagnosis. This review focuses on the evolution of wearable devices from benchtop electrochemical systems to microfluidic-based wearable sensors. Major classification of wearable sensors like skin contact-based and biofluidic-based sensors are discussed. Furthermore, sweat chemistry and related biomarkers are explained in addition to integration of microfluidic systems in wearable sweat sensors. At last, recent advances in wearable electrochemical sweat sensors are discussed, which includes tattoo-based, paper microfluidics, patches, wrist band, and belt-based wearable sensors.

As many as 200 kinds of volatile organic compounds (VOCs) are included in human exhaled breath. Many papers using VOCs as a biomarker of respiratory diseases have been reported. However, it is very difficult to measure very low concentration of VOCs in exhaled breath with high precision. Moreover, it is also difficult to distinguish VOCs in exhaled breath and VOCs in atmosphere. Therefore, measurement of VOCs is rarely used in a clinical field because complicated and large-sized system is required for measure VOCs in exhaled breath. We are developing exhaled breath measurement system which overcame these problems. Our system analyzes exhaled breath discharged from living body by inhaling atmosphere from which VOCs were removed. In this paper, results of system improvements are reported. At first, we adopted a cold trap method with dry ice as a method of purifying atmosphere (method A). Method A needs complicated device and long processing time. Next, we changed the method into solid absorbent from method A (method B). We verified purity of purified air. Concentration of 10 kinds of VOCs contained in both exhaled breath and atmosphere were measured. Selected VOCs are as follows: benzene, cyclohexane, ethylbenzene, heptanes, hexane, isoprene, nonane, octane, toluene and xylene. Atmosphere was purified by the method A and B. Concentrations of VOCs contained in the purified air were measured by gas chromatography. As a result of measurement, almost VOCs were not detected in the purified air made by both methods. Furthermore, time to make purified air was reduced from 70 minutes to 10 minutes. Simplification of the system and shorter processing time than method A were realized by method B while keeping purity.

Selected volatile organic compounds (VOCs), such as benzene (C6H6), cyclohexane (C6H12), isoprene (C5H8), cyclopropanone (C3H4O), propanol (C3H8O), and butyraldehyde butanal (C4H8O), in exhaled human breath can act as indicators or biomarkers of lung cancer diseases. Detection of such VOCs with low density would pave the way for an early diagnosis of the disease and thus early treatment and cure. In the present investigation, the density-functional theory (DFT) is applied to study the detection of the mentioned VOCs on Ti3C2TX MXenes, saturated with the functional groups Tx = O, F, S, and OH. For selectivity, comparative sensing of other interfering air molecules from exhaled breath, such as O2, N2, CO2, and H2O is further undertaken. Three functionalization (Tx = O, F, and S) are found promising for the selective detection of the studied VOCs, in particular Ti3C2O2 MXenes has shown distinct sensor response toward the C5H8, C6H6, C6H12, and C3H4O. The relatively strong physisorption (Eads≅-0.45to-0.65eV\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${E}_{ads}\\cong -0.45 to-0.65 {\ ext{eV}}$$\\end{document}), triggered between VOC and MXene due to an enhancement of van der Waals interaction, is found responsible to affect the near Fermi level states, which in turn controls the conductivity and consequently the sensor response. Meanwhile, such intermediate-strength interactions remain moderate to yield small desorption recovery time (of order τ≅μs-ms)\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ au \\cong \\mu {\ ext{s}}-{\ ext{ms}})$$\\end{document} using visible light at room temperature. Thus, Ti3C2O2 MXenes are found promising candidate material for reusable biosensor for the early diagnosis of lung cancer diseases through the VOC detection in exhaled breath.

Early disease detection and diagnosis through breath-based chemical assessment is broadly studied as a non-invasive tool and used as a cutting-edge opportunity in health care. Breath analytics or Breathomics is based on the recognition of levels of metabolites such as Volatile Organic Compounds (VOCs) and inorganic gases in an exhaled human breath. Lung cancer, one such disease state, alters the concentrations of hydrocarbons released in breath due to oxidative stress and lipid pre-oxidation. Heptane can be utilized as a VOC biomarker for the non-invasive diagnosis of lung cancer. This work outlines the fabrication of a graphitic carbon nitride-based electrochemical sensor platform that possesses increased catalytic activity and can be used for the screening of heptane vapors in the range of 0.45–5 ppm limit of detection of 0.45 ppm with 95% confidence interval. The synthesized material is characterized and validated using various standard analytical methods. Chronoamperometry is employed as an electrochemical technique to examine the diffusion dynamics of the target analyte. We demonstrated the specific sensing responses of the system in the presence of interferants by executing a cross-reactivity study with respect to other commonly found interferants in breath. We effectively established the use of a graphitic carbon nitride-based electrochemical sensor for point-of-care screening (qualitative analysis with p < 0.05) of heptane levels by the development of a prototype device utilizing a commercial microelectronic board. We envision that the in-house fabricated modified electrode platform can aid in early screening for lung cancer, thus leading to a reduction in the mortality rate.

Background/Objective: Cystic Fibrosis (CF) is the most common lethal genetic disease in Caucasians, but CF affects all races and ethnicities. A characteristic manifestation of CF is the pulmonary exacerbation (PEx), which involves an increase in pulmonary symptoms, decrease in pulmonary function, energy loss, weight loss, and changes to clinical findings, and correlates with lung disease progression and lower quality of life. However, in children with CF, PExs have a subtle presentation, similar to that of the cold or flu, and there is a need for a test that can identify PExs. For this project, our objective was to establish a proof of concept for the use of volatile organic compounds (VOCs) in exhaled breath as PEx biomarkers. Methods: This project enrolled 19 participants with a diagnosis of CF between the ages of 8 and 18, at Riley Cystic Fibrosis Center in Indianapolis. From each participant, exhaled breath was collected in a Tedlar Bag, in addition to lung function data and PEx status. Exhaled breath was analyzed for VOCs using Solid Phase Microextraction coupled to Gas Chromatography-Mass Spectrometry. Results: There were 13 VOCs that exhibited statistically significant differences in concentration between exhaled breath at baseline and during a PEx. These VOCs could be used in a Principal Component Analysis to differentiate baseline and PEx conditions. Finally, using Linear Regression, this project identified 22 VOCs with a significant correlation to lung function, an important potential confounder. Limitations include: (1) comparisons of multiple VOCs increase the likelihood of a false positive result and (2) small sample size. Conclusions: VOCs in exhaled breath are promising candidates as biomarkers to diagnose the presence and severity of PExs. In future experiments, we aim to expand the number of participants and track more clinical details to provide further evidence and applications for this proof of concept.

Introduction Human exhaled breath contains more than 1,000 of the vast variety of volatile organic compounds (VOCs), providing valuable information about the metabolic process in human beings. The information of breath could include current state of disease, leading to great potential of noninvasive diagnosis in medical industry 1-6. The concentration of the exhaled breath VOCs varies in sub-ppm or even lower in ppb level in healthy people7. However, when disease occurs in the human body, the metabolic process becomes disbalance. Hence, the concentration profile of exhaled breath VOCs drastically increases. Recently, deaths caused by lung cancer have reached 1.6 million each year8. Early screening and diagnosing of lung cancer are big challenges in the healthcare industry. There are many technologies to detect and diagnose lung cancer, such as low-dose chest computed tomography (CT), which enhances the likelihood of early-stage tumor diagnosis9, resulting in an increase in the survival rate10. However, the aforementioned technique still suffers from a large rate of false positive due to cross reactive responses10. In addition, due to the existence of a low dose of ionizing radiation in the CT, employing this technique increases the risk of cancer. Therefore, a noninvasive technology for breath analysis is desired to diagnose lung cancer. In this paper, we report a fast screening method of the lung cancer biomarker in exhaled breath by using gas chromatography-mass spectroscopy coupled with thermal desorption (TD-GC-MS), which is one of the noninvasive technologies that is able to perform this task. In the experiments, Tenax TA material is used as absorbent to absorb the exhaled breath VOCs, thermal desorption system is used to desorb the VOCs, which are separated by the gas chromatography column and further detected by the mass spectrometer. Method A 1 Liter Tedlar bag was used to sample the exhaled breath for the lung cancer patients at the NTU hospital Hsinchu. Further, the breath sample was transferred from Tedlar bag to Tenax TA tube with a flow rate of 40 cc/min for 25 minutes. An Agilent type7890A GC system with 5975C inert MSD with a triple-axis detector along with Perkin Elmer thermal desorption system (Turbo matrix 100) was used. Breath VOCs were separated by Elite-5 MS column (30 m × 0.25 mm, film thickness 0.25μm, Perkin Elmer) while working in a constant pressure mode (10 psi). The mass spectrometer was set to scan mode. The program of column temperature was maintained at 80 for 4 min, and then increased at a rate of 15 per min, to 230 and held at 230 for 4 min11. After breath sampling, Tenax TA absorbent was used to absorb the volatile organic compound, then the Tenax TA was connected to the Perkin Elmer thermal desorption system. Results and Conclusions Gas chromatography mass Spectro meter coupled with the thermal desorption system was used in the detection of lower concentration of the volatile organic compound in the exhaled breath for lung cancer patients. The thermal desorption process was used to desorb the volatile organic compound from the Tenax TA absorbent. The desorbed samples from Tenax TA absorbent were transferred through the column. The VOCs were moved into the column by the inert gas mobile phase; then, they were separated by the stationary phase fixed into the column. The separation efficiency depended upon the gas chromatography column. The detection principle of the GC-MS was based on the mass to charge ratio (M/Z) of the ionized atom for the detection of biomarkers in the lung cancer patients. After separation in gas chromatography, VOCs were detected by the mass spectrometer. The peak area of various kind of VOCs for lung cancer have been obtained. We have found some biomarkers from lung cancer’s exhaled breath such as acetone, toluene, ethyl benzene, decane, etc. In future, we will sample the breath for the control group, after analysis by GC-MS compare the result with lung cancer patient to identify the unique biomarkers. The Figure 1 shows the profile of the peak area with respect to the various kind of VOCs for the lung cancer patient. Therefore, the TD-GC-MS is an effective technique for noninvasive diagnosis by employing exhaled breath VOCs for the health care industry. These exhaled breath biomarkers can be used to screen the early lung cancerous disease to save millions of lives worldwide. Figure 1

Rationale: Currently, for the asthma syndrome no predictors of distinct phenotypes and future disease course exist. We aim to decode underlying mechanisms and to discover biomarkers for distinct wheeze and asthma phenotypes by measurements of volatile organic compounds (VOCs) in exhaled breath (EB) by gas chromatography-mass spectrometry (GC-MS). Methods: As part of the multi-centre All Age Asthma Cohort (ALLIANCE) of wheezing or asthmatic children and asthmatic adults, deep phenotyping is performed by comprehensive clinical assessment and ‘omics’ analyses. This includes measurements of the ‘breathome’ by analysis of VOCs in EB. Episodic viral wheeze (EVW), multiple-trigger wheeze (MTW) and asthma were defined per guidelines. During quiet tidal breathing, children inhaled pre-cleaned room air (RA) and exhaled into an aluminum reservoir tube. Together, RA and EB were loaded on adsorption tubes and shipped for analysis by GC-MS. Results: So far, 157 VOCs were assessed in EB and RA samples for 82 children (13 controls, 47 asthmatics, 10 with EVW, and 12 with MTW). Preliminary analyses show typical VOC compositions for EB (isoprene, acetone) and RA (propanols, ethanol). In univariate analyses, we found 20 VOCs to differ between asthmatics and controls, and 13 VOCs to differ between EVW and MTW after correction for multiple testing. Conclusions: Sampling of VOCs is feasible even in young children. The number of VOCs that differ between asthmatics and controls as well between wheeze phenotypes suggests that this non-invasive method will be an excellent complementary measure for in-depth characterization and identification of possible wheeze or asthma biomarkers and predictors in ALLIANCE.

Early diagnosis of lung cancer results in improved survival compared to diagnosis with more advanced disease. Early disease is not reliably indicated by symptoms. Because investigations such as bronchoscopy and needle biopsy have associated risks and substantial costs, they are not suitable for population screening. Hence new easily applicable tests, which can be used to screen individuals at risk, are required. Biomarker testing in exhaled breath samples is a simple, relatively inexpensive, non-invasive approach. Exhaled breath contains volatile and non-volatile organic compounds produced as end-products of metabolic processes and the composition of such compounds varies between healthy subjects and subjects with lung cancer. Many studies have analysed the patterns of these compounds in exhaled breath. In addition studies have also reported that the exhaled breath condensate (EBC) can reveal gene mutations or DNA abnormalities in patients with lung cancer. This review has summarised the scientific evidence demonstrating that lung cancer has distinct chemical profiles in exhaled breath and characteristic genetic changes in EBC. It is not yet possible to accurately identify individuals with lung cancer in at risk populations by any of these techniques. However, analysis of both volatile organic compounds in exhaled breath and of EBC have great potential to become clinically useful diagnostic and screening tools for early stage lung cancer detection.

Wearable sensors hold immense potential for real‐time and non‐destructive sensing of volatile organic compounds (VOCs), requiring both efficient sensing performance and robust mechanical properties. However, conventional colorimetric sensor arrays, acting as artificial olfactory systems for highly selective VOC profiling, often fail to meet these requirements simultaneously. Here, a high‐performance wearable sensor array for VOC visual detection is proposed by extrusion printing of hybrid inks containing surface‐functionalized sensing materials. Surface‐modified hydrophobic polydimethylsiloxane (PDMS) improves the humidity resistance and VOC sensitivity of PDMS‐coated dye/metal‐organic frameworks (MOFs) composites. It also enhances their dispersion within liquid PDMS matrix, thereby promoting the hybrid liquid as high‐quality extrusion‐printing inks. The inks enable direct and precise printing on diverse substrates, forming a uniform and high particle‐loading (70 wt%) film. The printed film on a flexible PDMS substrate demonstrates satisfactory flexibility and stretchability while retaining excellent sensing performance from dye/MOFs@PDMS particles. Further, the printed sensor array exhibits enhanced sensitivity to sub‐ppm VOC levels, remarkable resistance to high relative humidity (RH) of 90%, and the differentiation ability for eight distinct VOCs. Finally, the wearable sensor proves practical by in situ monitoring of wheat scab‐related VOC biomarkers. This study presents a versatile strategy for designing effective wearable gas sensors with widespread applications.

Cancer diagnosis by breath analysis: what is the future?