key: cord-0808425-9sb2unfz
authors: Vajhadin, Fereshteh; Mazloum‐Ardakani, Mohammad; Amini, Abass
title: Metal oxide‐based gas sensors for detection of exhaled breath markers
date: 2020-12-14
journal: Med Devices Sens
DOI: 10.1002/mds3.10161
sha: fb57de85c776f1095dc7f7d1cfd22d6b00c3daa6
doc_id: 808425
cord_uid: 9sb2unfz

Exhaled breath test is a typical disease monitoring method for replacing of blood and urine samples that may create discomfort for patients. To monitor exhaled breath markers, gas biomedical sensors have undergone rapid progresses for non‐invasive and point‐of‐care diagnostic devices. Among gas sensors, metal oxide‐based biomedical gas sensors have received remarkable attentions owing to their unique properties, such as high sensitivity, simple fabrication, miniaturization, portability, and real‐time monitoring. Herein, we reviewed the recent advances in chemoresistive metal oxide‐based gas sensors with ZnO, SnO(2), and In(2)O(3) as sensing materials for monitoring a range of exhaled breath markers (i.e., NO, H(2), H(2)S, acetone, isoprene, and formaldehyde). We focused on the strategies that improve the sensitivity and selectivity of metal oxide‐based gas sensors. The challenges to fabricate a functional gas sensor with high sensing performance along with suggestions are outlined.

metal oxides resulting in an increasing conductivity and reducing resistance. In the case of exposure to the oxidizing target gas, the overall result reduces the conductivity. In the p-type metal oxide, the adsorbed oxygen traps the electron through the valance band of metal oxide that results in generation holes. The effect of exposure to the reducing or oxidizing target gases on the conductivity is the reverse of n-type cases. Beyond n-type or P-type metal oxide as a sensing material, combining metal oxides with other metal oxides, noble metals, and carbon-based materials might generate p-p, n-p, and n-n type heterojunctions and potentially further enhance the electron mobility (Amiri, Roshan, Mirzaei, Neri, & Ayesh, 2020) .

Herein, we focus on MGS for disease diagnosis by EBM. Subsequent sections indicate the current state of gas sensors based on three most common metal oxides including ZnO, SnO 2 , and In 2 O 3 with paying attention to the role of nanomaterials for enhancing the analytical performance of the sensors.

We also describe recent progress in gas sensors along with the strategies to improve their sensing performance.

Exhaled breath composes of more than a thousand gases of which some of these gases are known as EBM that any variations in their concentrations initiate disorders and diseases. The most common EBM and their corresponding disease are briefed in Table 1 . As shown in some cases, the abnormality in EBM renders several diseases, while several EBMs might be attributed to particular diseases. Still the exploration of breath analysis in the clinics is very immature. There are great challenges for the standardization of EBM assessments that include but not limited to inter-individual variability stemming from genetics, human activities, or air pollutions. Despite such challenges, there is remarkable progress in revealing the connection between EBM and disorders (Guntner et al., 2019) .

The identification of acetone as EBM for diagnosis of diabetic people backs to 1857 (Crofford et al., 1977) resuming with continuous efforts on the investigation of EBM to accurately diagnose diseases. In a recent study, by taking benefits from data analysis methods, seven biomarkers for the discrimination of lung cancer patients from healthy ones were named as acetone, methyl acetate, isoprene, methyl vinyl ketone, cyclohexane, 2-methylheptane, cyclohexanone (Rudnicka, Kowalkowski, & Buszewski, 2019) . To date, by utilizing nanomaterials into sensors, the exhaled breath analysis has become more achievable for rapid and painless disease diagnostic.

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The analytical performance of gas sensors at the operating temperature and relative humidity (RH) is determined with the following characteristics. (i) Selectivity; The main challenge in MGS is selectivity for the accurate detection of EBM that often is modulated by the type and amount of dopants, grain size, morphologies, and preparation protocols (J. Kim, Kim, & Yong, 2012; S. J. Kim et al., 2016) . The selectivity of metal oxide-based gas sensors is often reduced in the interferences of water vapors(L. Liu et al., 2020) . It is of a note that the RH of human breath is about 89-97% (Ferrus, Guenard, Vardon, & Varene, 1980 Integration of these metal oxides with noble metal elements and carbon nanostructures is of important as it might lower their operational temperature to the room temperature. Table 2 summarizes recent MGS with their key characteristics for EBM detection.

ZnO is a very active semiconductor metal oxide for disease monitoring due to its excellent biocompatibility, low cost, and environment friendliness. ZnO morphology adjustment is important to maximize the interaction between the adsorbed oxygen and the target gas and thereby the sensitivity of MGS. Sensitivity and selectivity of ZnO-based metal oxides are often tailored via integration with other metal oxides (e.g., CuO) as well as noble metal elements that might tune Schottky barriers modulation and provide multiple p-n heterojunctions (J. Kim et al., 2012; Li et al., 2019) .

In recent years, the modification of ZnO with CuO for MGS has received remarkable attentions.

Various morphologies of ZnO-CuO nanocomposites were explored for MGS such as flower-like

This article is protected by copyright. All rights reserved (ethanol), nanorods (H 2 S) (J. Kim et al., 2012) and three-dimensional invers opal (3D IO) structures (acetone) (Xie, Xing, Li, Xu, & Song, 2015) . ZnO-CuO nanocomposites provide n-p type heterojunction that stems from a combination of ZnO (n-type) and CuO (p-type) where the fabrication of such heterojunction can lead to increasing resistance as an output signal when compared to pure ZnO and CuO (Xie et al., 2015) . 3D IO ZnO-CuO nanocomposite with well-ordered pores was evaluated for sensing acetone at LOD =0.1 ppm in breath. The acetone concentration in the exhaled breath of healthy people is approximately 0.3 to 0.9 ppm and in diabetes patients, type 1 and 2, are 2.2 ppm and 1.7 ppm, respectively, therefore, the latter sensor can meet the requirement of the proper dynamic linear range and LOD for diabetes diagnosis 

This article is protected by copyright. All rights reserved 3D IO ZnO response toward acetone was 2.2 times more than ZnO nanoparticles due to the large surface-to-volume ratio of 3D IO morphology that boosted the sensitivity by providing more active sites. The high operating temperature in these two works limits their practical applications for breath analysis as per their high-energy consumption and difficult operation. Importantly, high operating temperature reduces the discrimination capability of MGS in actual breath since voltaic organic compounds might be unstable and decomposed to other compounds.

Metal doping enhances the selectivity of gas sensors and amplifies the response toward the target gas 

This article is protected by copyright. All rights reserved . Therefore, developing MGS that enabled to work at room temperature is desirable. were studied in gas sensors. In an interesting study, the preparation of porous SnO 2 nanotubes was reported from SiO 2 -SnO 2 composites after SiO 2 etching followed by the decoration of exteriors and interiors walls with Pt nanoparticles (Fig. 2) Additionally, the selectivity of the gas sensor chip was evaluated in the presence of CO 2 and ethanol as interferences. Although the senor did not indicate enough selectivity in ethanol, the response was remarkable for the detection of H 2 in the presence of CO 2 . High operational temperature (150 ˚C in this case) might be the reason of the low selectivity of this sensor as the behavior of gases at high temperature is complex. Some images from this gas sensor chip is shown in Fig. 3 .

The low sensitivity of MGS particularly at high RH of the exhaled breath is one the greatest challenge of gas sensors. This is due to the presence of superficial hydroxyl groups on metal oxides that conclude in undesirable reactions with false results. To reduce the number of hydroxyl groups on metal oxide surfaces, dry synthesis of nanomaterials and high-temperature annealing are suggested (Vasiliev et al., 2018) . In a study, a spark discharge approach was applied for the dry synthesis of SnO 2 to generate airborne SnO 2 nanoparticles, which are separated with air gap for the purpose of H 2 detection (Vasiliev et al., 2018) . Additionally, surface saturation of metal oxide with hydroxyl groups could provide highly sensitive MGS at high RH since they do not adsorb more hydroxyl groups.

With a synergistic effect, the decoration of metal oxides with bimetallic nanoparticles is superior to their individuals for enhancing the sensitivity of MGS. Bimetallic nanoparticle decoration tailors

This article is protected by copyright. All rights reserved the surface electronic structure of metal oxide and reduces the activation surface energy, and as a result, facilitates the electron transport for sensitive target detection. Generally, to ensure the high

This article is protected by copyright. All rights reserved catalytic performance of bimetallic nanoparticles when integrated into MGS the size, morphology, dispersibility, and also compatibility of bimetallic nanoparticles with metal oxide substrate should be taken into consideration (S. J. Kim et al., 2017) . In a study, SnO 2 nanosheets with flower-like morphology decorated with PdAu bimetallic nanoparticles showed an excellent sensing platform for the detection of acetone at 250 ˚C with features of reusability and reliability at high RH (Li et al., 2019). PdAu-SnO 2 had the sensitivity towards formaldehyde at the temperature of 110 ˚C. This study highlighted the concern about the cross-sensitivity in an actual breath when the temperature is high. 

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The majority of current MGS suffered from low selectivity. Many researchers focus on the optimization of the experimental conditions to overcome this problem. However, developing MGS that relies on EBM separation with a filter and membrane holds a great promise for improving the selectivity of MGS, even in the cases that the materials do not have enough selectivity toward the target gas (Gregis et al., 2018) .

Reduced graphene oxide, as a two dimensional nanostructure, with excellent surface-to-volume ratio, low toxicity as well as outstanding electron mobility (200000 cm 2 V -1 S -1 ), have been widely utilized for disease monitoring (Feng, Li, & Wang, 2017; Lee, Lee, Hong, Lee, & Yoon, 2018; Vajhadin et al., 2020; Jinniu Zhang et al., 2018) . In addition to graphene, other two-dimensional materials such as 2D-SnSe 2 , Ti 3 C 2 MXene have employed for producing flexible MGS owing to light weight ,outstanding flexibility, and low-cost (Sun et al., 2020; Tannarana et al., 2020) . Recently, Lee et al.

reviewed carbon-based materials such as graphene oxide as a sensing substrate for the detection of NO 2 gas (Lee et al., 2018) . The nanocomposite of reduced graphene oxide and SnO 2 indicated the enhance sensitivity for ethanol detection compared with hollow SnO 2 nanostructures in humid and dry conditions ( Fig. 4) (Zito, Perfecto, & Volanti, 2017) .

This article is protected by copyright. All rights reserved The combination of reduced graphene oxide (p-type), polyaniline (p-type) and SnO 2 (n-type) served as a flexible sensing platform for the detection of very low concentration of H 2 S (0.05 ppm) (Fig. 5) (D. Zhang, Wu, & Zong, 2019). Data processing for the recognition of H 2 S through Principal Component Analysis (PCA) was beneficial to improve the quality and reliability of their sensor.

Generally, data analysis methods, including PCA, partial least squares (PLS), neural networks, and

Gaussian mixture models (GMMs), hold the potential to differentiate the target EBM among thousand EBM in exhaled breath (Rahman et al., 2020) .

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In 2 O 3 metal oxide has recently emerged as a promising metal oxide for MGS, however, its potential as a sensing material has been less exploited compared to ZnO and SnO 2 . In an interesting study, a portable gas sensor was fabricated using Pt@In 2 O 3 core-shell nanowires for real-time acetone measurement in exhaled breath (Fig. 6) 

Rapid advancement in MGS leads to non-invasive and rapid monitoring of diseases on the basis of EBM. In this study, we reviewed the latest advances in metal oxide-based gas sensors for the detection of EBM with a focus on ZnO, SnO 2 , In 2 O 3 owing to their unique sensing properties, satisfying stability and high compatibility for embedding into miniaturized chips. Despite progress in MGS, it is not profitable to use the majority of MGSs out of laboratories in a large scale. In fact, they

This article is protected by copyright. All rights reserved are in their infancy and much more efforts needed to produce portable MGS to accurately characterize EBM in the actual exhaled breath. Generally, the bottlenecks of current MGS are as follow: (i) poor selectivity due to the difficulty of recognition of EBM among various chemically similar molecules;

(ii) unreliable responses at high RH (⁓100%) that mimics the amount of moisture in the exhaled breath; (iii) high operational temperature that restrains the practical application of MGS for breath analysis. Coupling MGS with separation columns or membranes would significantly reduce the concern about the selectivity of current MGS. In addition, statistically processing MGS responses elevates the selective detection by MGS. Utilizing new humidity-resistance composites in MGS leads to functional MGS in the humidity of breath.

Covid-19 pandemic highlights that current diagnostic/treatment methods are not able to ensure the safety of medical staffs. Embedding functional gas medical sensor in the face masks hold great promise for the innovative medical devices that reduce the risk of disease transmission between medical staffs and patients (Ahmed, Harker, & Edirisinghe, 2020) . Fabrication of self-power MGS will facilitate the daily use of portable MGS for real-time breath analysis.

The authors thank Yazd University for the funding support.

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