Journal of Nanomedicine & Nanotechnology

On Non-Invasive Measurements of Exhaled Aceton Using Metal Oxide Nanosensors

Aroutiounian VM^* Yerevan State University, Yerevan, Armenia
^*Correspondence: Aroutiounian VM, Yerevan State University, Yerevan, Armenia, Tel: +37410555590, Email: ,

Received: 16-Feb-2021 Published: 25-Mar-2021, DOI: 10.35248/2157-7439.21.12.560

Introduction

Human breath is a complicated mixture of different gases including carbon dioxide, water vapor, oxygen, nitrogen, and trace levels of more than 1000 compounds which are either generated in the body (endogenous) or absorbed from the environment (exogenous) [1]. Human breath has been used as a potential tool for the diagnosis and study of diseases [2,3].The presence of biomarkers in the exhaled breath is suggestive for a number of medical conditions, such as lung cancer [4,5], breast cancer [6], asthma andchronic obstructivepulmonary disease (COPD) [7], and diabetes [8,9]. A few volatile organic compounds (VOCs) have been regarded as biomarkers to diagnose diseases, for example, formaldehyde and toluene (lung cancer), ammonia (hemodialysis), H₂S (halitosis), isoprene (heart disease), benzene (smoker), and pentane (acute asthma) are known as biomarkers for patients.

Recently, scientists have grown interested in solid-state sensors [10- 19] for detecting VOCs for non-invasive diabetes management. According to the World Health Organization, currently there are around 450 million peoples suffering from diabetes in the world, and this number could potentially reach 700 million by 2045. The number of patients with diabetes mellitus in Armenia today is 73 thousand.

As was mentioned above, human exhaled breath contains thousands of different volatile organic compounds (VOCs) derived from the body’s metabolic processes. In patients with diabetes mellitus, the body produces excess amounts of ketones [20] such as acetone because the body uses fats instead of glucose to produce energy, which is then exhaled during respiration. Endogenous acetone is produced in the liver primarily through ketogenesis. In certain cases, such as fasting, exercising and being diabetic, the liver produces ketones to act as an additional energy source, which is then metabolized into acetone and other ketone bodies. Using breath analysis techniques, acetone concentrations in the exhaled breath have been shown to correlate with the acetone concentrations in the blood as well as with other ketones such as beta-hydroxybutyrate.

Measurement of breath acetone may provide better diagnostic control of a patient's diabetic condition than using blood glucose alone [21]. At the same time, the detection of the concentration of acetone in the exhaled air can be carried out in a quick and acceptable way for the patient, alternative to the traditional methods for determining glucose in the blood. Many diabetic patients today have to check their blood sugar several times a day, which requires frequent and repeated pricking of their fingers, which is painful and unsafe. It has been established that glucose is also detected in the analysis of tears, saliva, and urine, but their corresponding meters at the commercial level are not yet available to patients.

So, acetone is considered today as the main breath biomarker for metabolic (diabetes) conditions in the bloodstream. It is found that the acetone concentration in exhaled breath of healthy people is ranged between 0.3 and 1. 0. ppm. Diabetes is one of the factors that may cause a change in breath acetone levels. Age, lifestyle, profession, and consuming ketogenic diet influenced breath acetone concentration and increase its concentration. Patients with typical symptoms of diabetes (polyuria, polydipsia and unexplained weight loss) have a high blood glucose concentration. Apart from hyperglycemia, hypoglycemia would damage the human body as well. Clinically, hypoglycemiais determined as a condition where the blood glucose concentration is lower. For elderly patients, the risk coefficient of hypoglycemia is higher. The incidence ofhypoglycemia at night is relatively high, and it is difficult to monitor it with traditional blood glucose detection methods. Strict blood glucose control is also likely to increase the risk of hypoglycemia. Therefore, continuous glucose monitoring in diabetics may be of more clinical application value and more in line with market trends [1,22].

Measurement of the concentration of acetone in breath is necessary. Techniques such as gas chromatography coupled to mass spectrometry, solid-phase microextraction, high-performance liquid chromatography, selected ion flow tube mass spectrometry, and liquid chromatography-mass spectrometry [4] for the detection of different gases. Sensors can be easy prepared by several who have provided a highly selective analysis of VOCs in the breath. Although mentioned above analytical methods are very sensitive and selective for diagnosis of diabetes mellitus, they are expensive, non-portable, and cannot be used out of hospitals.

Chemiresistors made from metal oxides

Metal oxide semiconductor gas sensors widely used today modern microelectronic technology methods, have low cost and high sensitivity [10-19]. Further research in this field is carried out in direction of the dramatica decrease of operating temperature from 300-500°C up to near-room temperature, understanding the phenomena on the surface of detectors, sensing mechanisms, and improvement of its selectivity to the gas. As electrical resistance in semiconductor metal oxide dramatically changes in the presence of an oxidizing or reducing gases, it is necessary often use only metal oxide-based chemiresistors for many applications. Several factors, such as surface areas, particle size, crystal defects, porous structures, and stoichiometry greatly affect the performance of such sensors. In particular, chemical gas sensors using various semiconducting metal oxides such as SnO₂, WO₃, ZnO, Fe₂O₃, and TiO₂, have been applied for acetone detection. Doping with metal or metal oxide and adding catalysts, particle size reducing, porosity and morphology controlling are used for the manufacturing of the most effective methods to improve gas sensing performance of the metal oxide semiconductor-based sensors. Some results of the best acetone detectors made of mentioned above semiconductors are discussed (see Table 1).

Table 1: Metal Oxides Based Acetone Sensors.

Chemiresistors made of tin dioxide

Tin dioxide SnO₂ with a wide band gap of 3.6 eV has been widely used to detect toxic chemicals such as CH₄, H₂, C₂H₅OH, gasoline, CO, C₂H₂, H₂O₂, NO₂, NO, NH₃, and H₂S. Pure (without impurities) SnO₂ and other metal oxide have low sensitivity to gases at its rather high pre-heating (operation) temperature. Doping of tin dioxide with some metals or carbon nanotubes is one way of improving the sensitivity of such metal oxide sensors. The sensitivity of SnO₂ sensors can be greatly improved by doping of the volume during a sensitizing of a material or dispersing on the oxide surface a low concentration of Co, Au, Pd, Pt, etc. For example, compared with sensors loaded with pure SnO₂ nanofibers, the Co-SnO₂ nanofiber sensors exhibited improved acetone sensing properties with high selectivity and rapid response and recovery times. Pure SnO₂nanofiber-based flat sensors have similar responses to acetone and ethanol. The Co-doped SnO₂ nanofiber-based flat sensors had more than five times larger response (sensitivity) than that of the sensors to ethanol. These results suggest that the addition of Co is beneficial to the selective acetone sensing properties of SnO₂nanofibers [6].

Acetone sensors made from SnO₂ doped with different impurities reported in [18,33]. A series of Co₃O₄-loaded tin dioxide nanocomposite thick films were prepared by grinding, screen printing and sintering in [34]. The composite films exhibited a good response to acetone at 300°C. At this temperature, the maximum sensor response to acetone (1000 ppm in the air) was 235, which was about 5 times as large as that of the pure SnO₂. The selectivity to acetone over H₂ and CO was also promoted by the addition of Co₃O₄ to SnO₂ [35]. Though Co₃O₄ is a p-type conductor and SnO₂ is a typical n-type conductor, the small mole rate of Co₃O₄ does not change it to a p-type. Measurements show an n-type response to reducing gases (the electrical resistance decreases on exposure to reducing gas) in air. The gas sensitivity exhibits a volcano-shaped relation with the operating temperature, reaching a maximum at 300°C in each case. The addition of Co₃O₄ does not result in a shift of the volcano-shaped correlations between gas response and temperature toward the lower temperature side. This is different from Ag₂O- and PdO-loaded SnO₂ sensors which makes the best operating temperature shift toward the lower temperature side [36,37]. Note again that the response of 5 mol.% Co to alcohol and acetone is far larger than that of pure SnO₂, proving a very marked promoting effect of Co₃O₄ loading. The sensor response of pure Co₃O₄ to several gases (1000 ppm) at 300°C is quite small compared to the sensor response of pure SnO₂. The sensor response degrades when excessive Co₃O₄ is added. Perhaps too many reactive sites make it more difficult for reducing gas molecules to disuse into the inner part of a thick film. At the optimal operating temperature of 180°C, the relationship between the sensitivity of the SnO₂ thick film and the acetone vapor concentration is shown in (Figure 2). The SnO₂ nanosensor is sensitive to low concentrations of acetone. T_A is the annealing temperature.

Figure 1: Response of sensors based on SnO₂ nanoparticles versus operating temperature to 1, 3, 5, and 10 ppm acetone, respectively.

Figure 2: The response dependence on the acetone concentration for SnO₂ powders at the operating temperature of 180°C [18].

The mechanism of sensitivity to acetone and the properties of SnO₂ thick films are discussed in [38]. Acetone vapor sensing characteristics of cobalt-doped SnO₂ thin films were reported in [39]. Structural and microstructural studies of PbO-doped SnO₂ sensor for the detection of methanol, propanol, and acetone were carried out in [40]. Gas sensors based on samarium oxide loaded mulberry shaped tin oxide for highly selective and sub-ppmlevel acetone detection were investigated in [41]. The response, selectivity, optimum operating temperature, response time, and recovery time were investigated in [42] for zinc, ceria, zinc with ceria doped and non-doped (pristine) SnO₂.

We discuss in [1,43] dimensional effects in small-size sensors. It was found also that the controlling particle size and porosity of the material can enhance the sensitivity of the material. Metal oxides with small grains, nanorods, nanotubes, nanowires, and so on can lead to the higher sensitivity of sensors made from them. The average grain size was reduced to several nanometers [1]. Tin oxide powders show higher sensor performance than corresponding metal oxide powder materials, which have a lower specific surface area. Microstructure plays a crucial role, and a sensor’s sensitivity can be significantly increased by using materials with very small grain sizes. The response was 33 when the sensors were exposed to acetone at 330°C. The response and recovery times to acetone were about 5 and 8 s, respectively [44].

For the detection of acetone, Choi et al. [45] used SnO₂ nanofilaments functionalized with reduced graphene oxide (RGO). A noticeable amount of acetone was achieved by increasing the RGO doping to 5 wt% and raising the operating temperature to 350° C. The predicted detection limit of acetone for these sensors at 5 wt% doping was only 100 bpm. Most likely, RGO formed continuous paths for the percolation of charged particles, which control electrical transport in nanofibers. The highly selective characteristics in the detection of acetone are apparently due to the combined synergistic effect of the porous nanotube morphology and the uniform distribution of Pt / PtOxnanocatalysts on thinwalled SnO₂ nanotubes (NTs), which can provide both chemical and electronic sensitization. In addition, in [45], sensors were developed with three different sensitive layers (NT Pt-PS SnO₂, NT Pt- SnO₂, and NT PS- SnO₂ [46-49].

A heterostructure acetone sensor made from NiO-doped SnO₂ hollow nanofilaments with porous structures through the combination of electrospinning technique and calcination procedure was developed [50]. The excellent sensing performances of the proposed sensor were ascribed to its hollow-core structure and Ni doping. In fact, the presence of heterojunctions formed by the combination of p-type NiO and n-type SnO₂ increased the sensor resistance and sensory responses to acetone vapor. The enhanced acetone sensing can be ascribed to the formation of p-n junction between p-type NiO and n-type SnO₂ grains. The gas sensor based on NiO- SnO₂ nanofibers has a maximum gas response at the operating temperature of 275°C, while the sensor based on NiO shows the highest responses at 325°C. NiO-SnO 2 exhibits a better selectivity than NiO, having a preferential response to acetone. Therefore, the NiO- SnO₂nanofibers could be used for selective acetone detection. Furthermore, the long-time stability of NiO and NiO- SnO₂ are also highly sensitive measured. Both sensors exhibit good stability towards 20 ppm acetone in 60 days. Acetone sensors based on SnO₂ , doped with Eu are reported in [51,52]. Work temperature was 280°C for such sensors. Y-doped SnO₂nanosensors were developed in [53].

Sensors made from metal oxides doped with carbon nanotubes (CNTs) have higher sensitivity and better stability of the sensor [8].

Acetone sensors made from SnO₂ <MWCNT>nanocomposites

It was shown in Yerevan State University [16] that the functionalized SnO₂ with multi-walled carbon nanotube (MWCNT) thick-film structures with Ru catalyzer leads to a considerable increase in response signal to the VOC gases. Structures were obtained by hydrothermal synthesis and sol-gel techniques as well as their combination. The choice of corresponding treating conditions and regimes for CNTs functionalization as well as thick film surface modification with Ru catalyst were focused in [16,54,55]. The testing of all samples at different operating temperatures in other to compare responses to various considered here target VOCs was carried out.

The largest and sufficiently selective response to acetone vapors (Ra/Rg = 1002) at their concentration of 1000 ppm is achieved at samples with 1:200 (MWCNT: SnO₂) mass ratio of the components. The largest response to acetone vapors (Ra/Rg = 555, 62) is fixed for such a set of samples to acetone vapors exposure 1000 ppm at 250°C operating temperature. Selective sensitivity of acetone vapors sensors with 1:50 mass ratio of the components appears only at the 300°C operating temperature.

As an example, the dependence of the 1:200 sensor response vs acetone vapor concentration at 150°C is presented in Figure 3. Note that the gas response increases linearly with acetone vapor concentration in its large range. It opens a possibility to realize an easy detector/measurer of the concentration of acetone in the air or exhaled breath gas.

Figure 3: Dependence of the SnO₂<MWCNT> sensor response vs acetone vapor concentration.

It is obvious today that the doping of metal oxide with CNTs leads to better sensitivity and lower preheating of the work body of a hybrid sensor. Note that several complicate phenomena processes take place in such functionalized nanocomposites. The full picture is not possible to propose today, but we have to take into account the following: MWCNTs have a huge specific surface area and a nanoscale structure, which exposes a large number of sites at which the gases can react. Detection of various gases can be provided at low temperatures of pre-heating of the work body of a sensor. The electric conductivity of CNTs is much higher in comparison with the conductivity of metal oxides. Therefore, CNTs reduce the resistance of the sensing metal oxide materials and open the possibility for the percolation of charge carriers through the sample. Since a metal oxide film has mainly n-type semiconductor characteristics and MWCNTs have p-type semiconductor characteristics, there are two depletion layers in such hybrid films. Note that the first depletion region is located at the metal oxide surface and the second one is located in the interface between the metal oxide nanoparticle and the MWCNTs. Formation of nanochannels and heterojunctions leads to enhanced gas sensitivity of such hybridized gas sensors as the decrease in the work function (barrier height) or increase in the conductivity of the metal oxide sensitive layer leads to the improvement in the performance of the gas sensor at low operating temperature.

The response of the prepared sensor toward 1 ppm acetone vapor at 250°C was presented in Figure 4. It is shown that the resistance decreases very sharply after exposure of acetone.

The addition of MWCNTs improves significantly the sensitivity of SnO₂. The sensitivity study was carried out for different concentrations of MWCNT to get the highest response as shown in Figure 4b. It is to be noted that the highest sensitivity was achieved for SnO₂ loaded in 0.25% MWCNTs. The over-addition of MWCNTs in the composite decreases the resistance of the sensor sharply. For over-addition of MWCNTs, the increasing number of electrons in the grain boundary reduce the resistance and increase the sensitivity of the sensors. The response toward acetone vapor was jumped to 72% after the addition of 0.25% MWCNT. The response of sensors made from pure nanocrystalline SnO₂ and SnO₂ loaded in 0.25% MWCNTs toward 1 ppm acetone for different operating temperatures is shown in Figure 4c. 0.25% MWCNT loaded SnO₂ sensor showed a much better response at the lower temperature. The sub-ppm level acetone sensing at 350°C is presented in Figure 4d.

Figure 4(a) The response of SnO₂ and SnO₂<0.25% MWCNT> sensors in 1 ppm acetone at 250°C.
(b) The response of SnO₂ sensor in 1 ppm acetone for different CNT loadings at 250°C.
(c) The response of SnO₂ and SnO₂<0.25% MWCNT>nanocomposite sensors in 1 ppm acetone at different temperatures.
(d) The response of SnO₂ and SnO₂<0.25% MWCNT> sensors in different concentrations of acetone at 350°C.

Note that nanonsensors to hydrogen dioxide made of SnO₂<MWCNT> were reported also in [14,16,17] and ZnO<CNT>-in [56]. Ahmadnia-Feyzabad et al. [57] also fabricated multiwall carbon nanotubes 1:200 MWCNT/ SnO₂ sensors using the ultrasonic-assisted deposition-precipitation method and they were used for detection of four VOCs, including acetone.

Significant enhancement of the sensor selectivity to acetone with respect to gases like toluene and trichloroethylene was observed. Narjinaryet al. [57] developed highly sensitive and stable acetone sensor by using MWCNTs as a substrate for sol-gel prepared nanocrystalline SnO₂. It was mentioned that the enhancement in sensing performance was due to the formation of hetero-junction and an increase in adsorptioncapacity because of the higher surface area of MWCNT.

WO₃ Based Chemiresistors

N-type tungsten trioxide (WO₃) with a bandgap of 2.6 eV is known as a promising material for VOCs sensing. Although most of the reported WO₃ gas sensors are based on its gamma- phase [58], epsilon- WO₃ is used for selective and sensitive detection of acetone in ppb concentrations which is attributed to the spontaneous electric dipole moment of the epsilon–phase that increases the interaction with analytes having high dipole moment. Wang et al. synthesized epsilon - WO₃ nanoparticles by means of flame spray pyrolysis. Cr dopants were used to stabilize the epsilon _ phase [59]. Si-doped WO₃chemoresistive sensors were used to thermally stabilize the acetone selective epsilon - WO₃ phase at the operating temperatures 300-500_C as an alternative to doping with potentially toxic Cr [27-38]. Righettoni et al. [60] developed a portable exhaled breath acetone sensor based on a back-heated substrate with a sensing film of WO₃ nanoparticles doped with Si. The sensor could detect acetone even at low concentrations up to 20 ppb. Güntner et al. [61] developed an WO₃:Si acetone sensor combining with a sampler that extracted and buffered the end-tidal fraction of breath. This sampler was applied for prolonged sensor exposure.

In past years, the researches were prepared most of the WO₃ sensors by methods sol-gel, electrospinning, hydrothermal and glancing angle deposition methodology. They have been used to improve acetone sensing characteristics [62–64]. The advantages and disadvantages of different techniques are summarized in Table 1 [1]. In addition to morphology control, doping and dimension control are used to improve the gas sensitivity and selectivity of WO₃. For example, Gao et al. [65] prepared Cr2O₃-doped WO₃ thin films by sol–gel method. The acetone sensing properties are a function of the porous structure, the Cr2O₃ content, the sintering temperature and the cooling way. Xiao et al. [66] prepared Cudoped WO₃ hollow fibers by electrospinning technique, combined with the sol–gel method.

Choi et al. [67] prepared bumpy WO₃hemitube nanostructure via O₂ plasma surface modification of electrospun fiber templates. The WO₃ hemitubes were functionalized with graphene-based material utilizing either thin graphite (GR) or graphene oxide (RGO) layers for the detection of acetone and hydrogen sulfide (H₂S). The sensing properties of the GR (0.1 wt %)- WO₃ and GO (0.1 wt %)-WO₃ hemitube sensors were investigated in highly humid ambient (85−95% RH) and the sensors exhibited highly H₂S as well as acetone selective characteristics with respect to various interfering biomarker gases. The superior sensing properties were ascribed to the electronic sensitization of graphene based materials by modulating space charged layers at the interfaces between n-type WO₃ hemitubes and p-type graphene-based materials. The use of graphene-based additives significantly enhanced the acetone sensing characteristics of such composite materials for exhaled breath analysis.

Better gas sensing properties of Cu-doped triclinic WO₃ hollow fibers were attributed to the high surface-to-volume ratio of WO₃ hollow fiber, junction structure, and triclinic phase composition, which strengthened the interaction between acetone and WO₃ on the surface.

Xiao et al. [70] synthesized C-doped WO₃ polycrystalline materials by using cotton fibers as a template and carbon source. The C-doped WO₃sensor showed good long term stability. Upadhyay et al. [71] developed a new acetone sensor based on In-doped WO₃ nanostructures. The increasing of the responses to acetone vapor was connected with the change in the surface morphology of the WO₃ upon indium doping which affects the extent of adsorption of atmospheric oxygen on the surface of sensors.

1D WO₃ nanotubes with the average diameter of about 200 nm by electrospinning were synthesized. The surface of the produced nanotubes was rough and full of protuberances which could provide more space for electrons on the surface of WO₃ to react with target gas and makes an enhancement in the sensitivity. WO₃nanofibers with a porous morphology by electrospinning method were prepared. They allowed detection of acetone down to 0.1 ppm even at 95% relative humidity. The Si-doped WO₃, WO₃nanofiber scaffold and WO₃/Pt-decorated rGO nanosheets were also applied for acetone sensing. [69-71]. Shen et al. alsosynthesized hierarchical walnut-like Fe-C-codoped WO₃microspheres for application in the breath acetone analysis. The amount of Fe doping was optimized based on detecting the acetone responses dependent on the operating temperature and exhibited high response to acetone and very low responses to NH₃, CO, toluene, methanol, ethanol and NO.

Other promising research efforts in developing highly selective and sensitive exhaled breath sensors are combining noble catalysts and unique metal oxide nanostructures [73,74]. Selective detection, high surface area and high porosity are some of several advantages of this approach. For instance, Shin et al. [75] synthesized polycrystalline WO₃ fibers functionalized by catalytic Pt and IrO₂ nanoparticles to prepare chemiresistive sensors for exhaled breath analyses of diabetes and halitosis by detecting acetone and H₂S in a humid atmosphere (RH 75%). The Pt-WO₃ fibers showed a higher acetone response and also a superior response to H₂S compared to pristine WO₃ fibers. Beside, IrO₂- WO₃ fibers showed the temperature-independent sensing properties and selective response to H₂S. Thus, the highly selective cross-response between H₂S and acetone was successfully achieved via the combination of IrO₂ particles on WO₃ fibers. This group suggests the p-type semiconductor property of PtO (0.86 eV) and the n-type semiconductor property of IrO₂ (2.34 eV) resulted in totally distinct sensor properties driven by chemical sensitization and electrical sensitization, respectively. Choi et al. [75] synthesized thin-walled WO₃ hemitube and catalytic Pt functionalized WO₃ hemitubes via a polymeric fiber-templating route for the detection of H₂S and acetone. WO₃ hemitubes showed superior hydrogen sulfide sensing properties with minimal response to acetone and toluene at 85 RH% while Pt functionalized WO₃ hemitubes exhibited superior acetone response with negligible H₂S response. As mentioned above, small crystal size and large specific surface area are definitely advantageous to improve gas sensing response. Kim et al. [78] prepared WO₃nanofibers (NFs) functionalized by Rh2O₃ nanoparticles (NPs) with high sensing properties toward acetone at humid atmosphere (95%). The increased oxygen vacancies in WO₃, caused by functionalization of Rh2O₃ NPs and catalytic sensitization of Rh2O₃ NPs on WO₃ NFs were discussed as the reasons for the improved sensing properties of the fabricated sensor. Yin et al. [78] developed RuO₂ NPs loaded WO₃ NFs for potential diagnosis of diabetes. Recently, studies using apoferritin as a protein template have been researched for uniform loading of catalyst NPs on supporting scaffold layers. Apoferritin is a sphere-shaped protein with the size of 12 nm consisting of 24 protein subunits. It includes a sphere-shaped inner cavity with 7–8 nm in diameter, which can encapsulate ions and metal within the hollow cage. Importantly, the outer surface of apoferrit in is positively charged, generating repulsive force between individual apoferritins to induce well dispersed apoferritins. Apoferritin as a suitable template and electrospining as an effective method for nanofiber synthesis were employed for the preparation of sensing material. The improved acetone gas response of the fabricated sensor was attributed to electronic sensitization behavior of RuO₂ and the increased oxygen vacancies generated by RuO₂.

The design and control of the surface state is another possible way to obtain good gas sensitivity and selectivity. Different crystallographic facets corresponding to different shapes of metal oxides have distinctive surface atom structures and surface energies, which have been demonstrated in the chemical reactivity and sensing property of nano- and microsized crystals. So, it is momentous to predict and control the exposed facets and investigate the facet-dependent sensing properties of metal oxides [78-80]. For instance, Jia et al. [77] synthesized WO₃ nanorods with exposed (100) and (002) facets via a hydrothermal approach using different directing agents and the effect of exposed facets on acetone sensing properties were investigated. It was realized that WO₃ samples with exposed (002) facets exhibited better acetone sensitivity and selectivity than those with (100) facets against ethanol and other reducing gases. They stated that the asymmetric distribution of unsaturated coordinated O atoms in the O-terminated (002) facets, leads to distortion of the electron cloud and production of local electric dipole moment on the surface. This local electric dipole moment increases the interaction with analytes having high dipole moment (e.g., acetone) which brings selectivity to WO₃nanorods with exposed (002) facets. In addition, high gas sensitivity is a consequence of the large number of oxygen vacancies and defects on the (002) facets [81]. Al-Hadeethi et al. [82] successfully synthesized cuboid WO₃nanosheets with exposed (020) and (200) facets by a low-temperature acid-assisted (HCl) hydrothermal process. The high acetone selectivity was related to the asymmetric arrangement of O atoms on the exposure facets, which cause the non-uniform distribution of electron cloud on the exposed facets. The high sensitivity of WO₃nanosheets to the organic vapors with high dipole moment is due to the local electric polarization on the exposed facets. Alizadeh et al. [1] II data about the optimum temperature, response and recovery times and detection limits of some developed WO₃ acetone sensors are collected in Table 1 [1].

The sensing response of pure WO₃ and C-doped WO₃sintered at different temperatures to acetone in the concentration range of 0.2–5 ppm at operating temperature 300°C is shown in Figure 5.

Figure 5: The sensing response of pure WO₃ and C-doped WO₃ sintered at different temperatures to acetone in the concentration range of 0.2–5 ppm at operating temperature 300°C.

ZnO Based Chemiresistors

Zinc oxide (ZnO) is an inorganic compound with a wide bandgap 3.3 eV. ZnO has attracted considerable attention because of its good response to different gases [47,80,81]. Doping with different metals such as Sn [83], Mn [83,84], Co [85], Ni [86], Cr [87], Rh [88], Al [89], rare earth metal [32], [90], CuO [91] and also utilization of noble metal such as Au [92–94] and Pt [95] led to improve response of ZnO-based acetone detectors (see Figure 6). Rare earth metals, such as La and Ce, due to their excellent catalytic properties, have been utilized as sensitizers because they can increase the number of active sites on the surface of semiconducting oxides.Taking into account that Au nanoparticles can activate the dissociation of molecular oxygen, the enhanced sensing properties were obtained [96]. Various ZnO quantumdots and nanocomposites have been introduced for acetone detection such as ZnFe₂O₄ [97-99], Zn₂SnO₄ [100], ZnSnO₃ [101], ZnO-CuO [102], SnO₂-ZnO [103-104], ZnO/ZnCo₂O₄ [105], ZnO/graphene [106–108], ZnO-CuO/graphene oxide [109], graphene-ZnFe₂O₄ [110] and ZnO– In₂O₃ [111].

Figure 6: Highly selective real-time detection of breath acetone by using ZnO quantum dotwith a miniaturized gas chromatographic column.

ZnO based acetone sensors have various forms, such as thin films, nanofibers, nanorods, nanowires, porous nanoparticlesetc. [91-96]. Highly selective detection of acetone in respiration was observed in a ZnO sensor with quantum dots. Improved sensing properties to acetone shown solid and hollow ZnO nanofibers [91], snowflake - like ZnO structures [43]. Various hierarchical ZnO architectures, including dumbbell-like ZnO [97], dandelon-like [98], flower-like [99,100], porous rectangular plate [101], hollow nano cage [102] and nano comb [44] have been prepared by different methods for acetone detection. The dandelion-like ZnO gas sensor to acetone exhibited remarkable selectivity for acetone in 90% of relative humidity (RH) and good selectivity towards acetone concentration of higher than 10 ppm [97]. The synthesis of stable three-dimensional (3D) hierarchically assembled porous uniform rectangular ZnO plate It was reported. Chen et al. proposed a hierarchical nan comb structure ZnO gas sensor for the task of acetone detection [102]. Li et al. synthesized hierarchical hollow ZnOnanocages which could detect acetone in ppb level with good selectivity [95].

Fe₂O₃ Based Chemiresistors

Hematite (α-Fe₂O₃) which is the most stable iron oxide under ambient conditions. The information about Fe₂O₃chemiresistors collected in [1]. Remarkable efforts have been allocated to the construction of α-Fe₂O₃ based sensors sensitive to acetone [ Ma et al. [112], Sun et al. [113], Guo et al. [114]. The enhanced sensing properties were connected with wide porous distribution of the nanoscale Fe₂O₃, small particle size, high surface area., and formation of sufficient electron depletion area.

Successfully synthesized hollow and porous Fe₂O₃ nanotubes were realized by a single nozzle electro spinning method following with annealing process. Kim et al. [115] studied hematite nanotube array synthesized by anodization method. Gunawanet al. [116] synthesized Au-decorated 1D Fe₂O₃ acetone sensors via microwave irradiation method. The presence of Au NPs is elevated the dissociation of O₂ better in replenishing O vacancies, thereby increasing the immediate supply of lattice oxygen to the oxidation of acetone, which leads to ultra-high sensitivity towards acetone. Shan et al. [117] investigated the effect of La doping on the acetone sensing behavior of Fe₂O₃ nanotubes. Electro spinning followed by calcination led to enhancement in the electrical transport properties of the sensor due to the presence of La, reduction of the grain size and so enlargement in surface sites for reactions and the catalytic activity of La for the conversion of the reducing gas into the respective oxidation product.

The response of the sensor to acetone was depended on humidity and decreased by increasing the RH. Liu et al. [118] compared the acetone sensing properties of electrospuned pristine and Ce doped α- Fe₂O₃ nanotubes. They explained the better acetone sensitivity of Ce doped Fe₂O₃ nanotubes by the formation of more defect on the surface of Fe₂O₃ nanotube after doping Ce(IV) could lead to a larger contact area between acetone and sensing material and also the catalytic behavior of Ce for the conversion of the reducing gas into the respective oxidation product. Jin et al. [119] reported the synthesis and sensing characterization of monodisperse porous pure and Cu-doped Fe₂O₃microcubes, microcakes and microspheroids. The improved acetone sensing properties of Cu-doped Fe₂O₃ particles than the pure one was relevant to the increasing active sites in doped particles, large surface area, pore size, and catalytic properties of Cu. Chakraborty et al. [120] used sonochemically prepared nanosized Fe₂O₃ sensors to detect human breath. Biswal [121] synthesized pure and Pt-loaded nanocrystalline Fe₂O₃ by precipitation using ultrasonic irradiation. He observed 55% enhancement in response to acetone by the addition of 1wt% Pt to alfa- Fe₂O₃. 1D/2D α- Fe₂O₃/SnO₂ hybrid nanoarrays for subppm acetone detection were investigated in [122]. The response on NiO, α-Fe₂O₃, and α-Fe₂O₃ / NiO samples per 100 ppm acetone at different operating temperatures is shown in Figure 7 (see [123]). Improved gas-sensitive characteristics in acetone were observed in nanowires (rods) from α-Fe₂O₃ / NiO heterojunctions[123].

Figure 7: α-Fe₂O₃/NiO heterojunctionnanorods with enhanced gas sensing performance for acetone.

The results of response measurements for a patented acetone sensor shown in Figure 8 [53], a composition for detecting acetone for it, and a method for its preparation of which is proposed. The composition includes Y-iron oxide (Y-Fe₂O₃), antimony salt and platinum (Pt) contacts. The inventors noted that a sensor made using the above formulation is selective for a low concentration of acetone for respiration. In this US patent, measurements were carried out in a very small, unsatisfactory for practice, acetone concentration is 0.75-1.25 ppm (Figure 8). Perhaps such semiconductor sensors for diabetes monitoring are non-invasive, but expensive. The measurements of the characteristics of sensors based on Y-Fe-O were carried out at an operating temperature of 300°C.

Figure 8: A type of an acetone microelectronic monitor.

In₂O₃ Based Chemiresistors

Indium oxide (In₂O₃) is an n-type semiconductor with a wide bandgap of 3.55–3.75 eV. Their sensing performance improvement can be realized by involving of Au [124–128], Pt[129], Pd[130] on the surface of this material. Various In₂O₃ based gas sensors with different morphologies such as sphere nanoparticles [131,132], hollow nanofiber[133], porous hollow spheres [49], hierarchical nanostructure [134-144], nanowire and nanotube [124] have been developed for acetone detection. Xing et al. [124] fabricated the ordered three-dimensional inverse opal (3DIO) macroporous In₂O₃ films to determine acetone detection in human breath. Theyproposed three-dimensional In₂O₃–CuO inverse opals for selective acetone detection.

TiO₂ Based Chemiresistors

Titanium dioxide (TiO₂) has the stability, low-cost, and nontoxicity. TiO₂ is usually a stable n-type material in the rutile phase. However, some reports are published on sol–gel derived undoped p-type TiO₂ thin film with anatase phase. The non-stoichiometric p-type TiO₂ originates either from Ti vacancy or from oxygen interstitials [145]. Rell et al. [146] developed a new technique for the deposition of TiO₂nanoparticle thin films - matrix-assisted pulsed laser evaporation for gas sensor manufacture. The proposed technology allowed to detect both vapors of acetone and ethanol at low concentrations (20–200 ppm in dry air). Deng et al. [147] realized a TiO₂nanoporous thin film based gas sensors and detected 1.5 ppm acetone under the interference of water vapor. Ding et al. [148] fabricated a microsized room temperature acetone sensor on photoinduced SWNT−TiO₂ nanohybrid with core/shell structure using screen printing of the commercial P25 TiO₂ paste. Such chemiresistor showed linear, fast and reversible responses to acetone at ppm-level. The screen-printed titanium dioxide (TiO₂) sensor showed sensitivity for type 1 diabetes diagnosis.

Teleki et al. [149] produced nanostructured anatase TiO₂ by flame spray pyrolysis and tested for sensing to of volatile acetone at 500°C. Yang et al. [150] synthesized novel anatase TiO₂ hierarchical microspheres with selectively etched high-energy (001) crystal facets by a facile hydrothermal method and detected a much higher acetone response than that of TiO₂ microspheres with intact (001) facets and slightly-etched (001) facets. They proposed that (001) facets could act as active sites for gas absorption and facilitate the gas sensing reaction.

Acetone detectors made from chemisistors based on oxides of other metals are discussed in the literature. Note that there are other metal oxide-based chemi-resistive exhaled air sensors for potential use in the diagnosis of diabetes mellitus using acetone as a biomarker. Sensors with a sufficiently high response (S=Ra/Rg) to acetone have also been implemented on the following nanostructures: Fe₂O₃ / Al - ZnOnanocomposites, SnO₂ / Au-In₂O₃ core-shell nanofibers, SnO₂-Sm2O₃ hierarchical structures, ruthenium-doped NiO balls in the shape of a flower, NiO spheres doped with W, Sm2O₃/SnO₂, TiO₂ nanoparticles on In₂O₃nanocrystals.

Note that the choice of chemiresistive acetone sensors based on metal oxide materials (including nanostructures) is already very large. Which of these sensors will be used in real devices depends on their many parameters and, of course, on the cost of nanostructures.

Non-invasive diagnosis of deceases

Diabetes mellitus belongs to the global medical and social problems of the XXI century, which have affected the entire world community. According to the World Health Organization, the number of registered diabetes patients in the world is about 450 million peoples. Diabetes mellitus (DM) is a syndrome of impaired carbohydrate, fat, and protein metabolism caused by either lack of insulin secretion or decreased the sensitivity of the tissues to insulin. Relating this it is categorized as type I diabetes (It is called insulin-dependent diabetes mellitus (IDDM) and is caused by lack of insulin secretion) and type II diabetes ( It is called non–insulin-dependent diabetes mellitus (NIDDM) and is caused by decreased sensitivity oftarget tissues to the metabolic effect of insulin). This reducedsensitivity to insulin is often called insulin resistance. In both types of diabetes mellitus, metabolism of all the main foodstuffs is altered.

When analyzing the effects of acetone on diabetic patients, it would probably make sense to start from the concentration of acetone 1 ppm. Most diabetics are at a relatively early stage of the disease (the concentration of released acetone is up to 10-12 ppm), basically they are not under the daily supervision of doctors. A miniature and easy transportable glucose (sugar) meter is needed for such patients. The dependence of the response of the gas sensor on the concentration of acetone for a healthy and sick person is shown in Figure 9 [151].

Figure 9: “Healthy” and “diabetic” regions in the sensor of silicon-doped WO₃ acetone [151].

The analysis of the acetone influence for diabetic subjects has the sense to make starting 1 ppm. A type of an acetone microelectronic monitor is shown in Figure 8. For its implementation, it is necessary to have, for example, such a metal oxide sensor with a high sensitivity to acetone of the type as measured by Dr. A. Sayunts at YSU in the concentration range of 1-12 ppm on our sensor made of SnO₂<MWCNT> (see Figure 9).

We proposed early semiconductor monitors, including those using Arduino Nano processors [152-154]. Note that for the implementation of a non-invasive monitor of acetone with a tube, such as shown in Figure 8, it is additionally necessary to develop the latter with a special mouthpiece or another device that dries out the patient's exhaled air. High humidity of exhaled air created often corresponding higher requirements to sensors. Therefore, it is necessary to develop a pre-concentrator to its. The pre-concentration technique is well known in chromatography where the separation column is filled with adsorbent molecules. The same mechanism is mostly applied for pre-concentrators to exhaled biomarkers. Two-step pre-concentration in order to reduce the humidity level in exhaled samples is preferable today.

Conclusion

Recently, interest has increased in semiconductor gas sensors for non-invasive control of various human diseases. The paper presents and discusses the work carried out on non-invasive metal oxide sensors (chemiresistors) for acetone exhaled by a diabetic both at Yerevan State University and abroad. Such sensors are manufactured using the methods of modern microelectronic technology. They have a low cost and high sensitivity to gas. The technologies and parameters of chemiresistors based on tin dioxide, tungsten trioxide, zinc oxide, Fe₂O₃, In₂O₃, and TiO₂ developed at YSU and in the world are presented. When analyzing the effects of acetone on diabetic patients, it is most likely to start with an acetone concentration of 1 ppm. At YSU, the response of chemiresistors made of SnO₂ doped with MWCNT was measured at a concentration of acetone released from 1 to 12 ppm, typical for diabetics at a relatively early stage of the disease. Microelectronic glucose (sugar) meter is needed.

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