Metal Oxide Gas Biomarkers of Diseases for Medical and Health Applications

be used for sensors to diagnose various diseases. Non-invasive diagnostics of the patient, based on the analysis of exhaled air in a special device, allow only to make exhalation and after a few seconds-one minute to get the results of the analysis. The prospect of a non-invasive diagnosis is obvious - full safety from viral hepatitis, AIDS, and other infections. Exhaled breath contains about 3500 volatile organic compounds (VOCs) that are the products of metabolism. But it is necessary to take into account that several important gases at some concentration in the air are immediately dangerous to life or health. According to the results of the study of volatile substances exhaled by a person, it is possible to judge the nature of nutrition - sufficiency of carbohydrates, excess fat and alcohol. By excess or lack of any chemical component in the spectrum of exhaled air, hereditary enzymopathy and the presence of various diseases can also be assumed. Due to the large surface of the lungs, volatile substances (ethanol, ammonia, acetone, and others) very quickly pass from the bloodstream to the external environment with exhaled air. It is the mixture of various molecules secreted by a man that makes up the individual, unique smell of the patient. In a number of cases, this smell allows to immediately make the correct diagnosis. The sweet “liver odor” of explosives is due to a violation of the exchange of aromatic compounds and the accumulation of the product of the conversion of methionine - methyl mercaptan. This One of the most important directions of modern medicine is non-invasive diagnostics of the patient, based on the analysis of exhaled air in a special device. Data on the surveillance capabilities of various diseases in the allocation of specific gases are collected. The potential of various semiconductor chemical resistors made from metal oxide semiconductors to diagnose disease has been reviewed. Corresponding low-cost detectors are developed which can detect small concentrations of exhaled air. (diagnose) cancer stomach and ovaries, rheumatoid disease, myocardial infarction, decay, bacterial imbalance the teeth, dehydration, sleep apnea, gastric, presence

Besides, in the case of a healthy person, the exhaled air contains rather small concentrations of nitric oxide NO, ammonia NH 3 , carbon monoxide CO, hydrogen dioxide H 2 O 2 and sulphide H 2 S as well as ethanol, acetone, etc. A remarkable increase in the concentration of last gases indicates the presence of various diseases in the patient. The metabolic excreted products diffuse into the inhaled air though the alveoli in the lungs and then the air is rejected. That is, a multi-component gas mixture formed, which accumulates first in the alveolus of the lungs. It is necessary to look for the cause of this either in incoming food (sources of volatile substances), or in internal organs, blood, blood vessels, sweat or urine. Today the medical doctor not only polls and examines the patient but also sends it to the lab-tests of blood, urine, perform an electrocardiogram, etc. But, for example, today's periodic monitoring of glucose concentrations in the blood induces acute pain, risk of virus (e.g., hepatitis B) infection from needles, and other difficulties infrequent monitoring. It is the mixture of various molecules secreted by a man that makes up the individual, unique smell of the patient. In a number of cases, this smell allows to immediately make the correct diagnosis.
The sweet "liver odor" of explosives is due to a violation of the exchange of aromatic compounds and the accumulation of the product of the conversion of methionine -methyl mercaptan. This

ARTICLE INFO AbsTRACT
smell of raw liver often haunts pancreatic cancer patients and may be one of the first symptoms of this ailment. The smell of ammonia in explosives is typical for kidney and uremia diseases, the "mouse smell" -for patients with hereditary phenylketonuria, the smell of syrup is in violation of the metabolism of fatty acids and the accumulation of keto acids and amino acids in the blood and urine, the smell of acetone -in patients with diabetes mellitus. A sharp specific smell from the mouth is a symptom of a number of diseases of the oral cavity and stomach (stomatitis, periodontal disease, gastritis, peptic ulcer, and stomach cancer).
In cardiopulmonary insufficiency, unpleasant sour smell of under oxidized metabolic products associated with incomplete combustion of proteins, fats, and carbohydrates in the liver often comes from patients. An unusual persistent smell is a formidable symptom of a growing tumor of the anterior brain. It turned out that with a stroke with an unfavorable outcome, much less acetone is released in patients than in healthy people. At the same time, diabetics, who also fell into a coma, exhale tens and hundreds of times more acetone than healthy ones. The content of acetone and ethanol is significantly different from healthy individuals (in patients with diabetes mellitus, cardiovascular disease, in children with bronchial asthma, diathesis, in pregnant women with toxicities of the first half of pregnancy). We also note that it is possible to successfully detect using semiconductor sensors odorless substances, such as carbon monoxide (carbon monoxide) or carbon dioxide.

Capabilities of Detection of Various Diseases
Capabilities of detection of the various diseases using the analysis of the breath are discussed below. Data on the surveillance capabilities of diseases in the allocation of specific gases are collected below in Table 1

Methods of the Study of the Compositions of Explosives
From the middle of the 20th century to the present day, chromatography and mass spectrograph are among the most widely used analytical methods for studying explosives [1][2][3][4][5]. Many volatile metabolites were determined by these methods in explosives, many of which are used as markers of inflammation. Their specificity and sensitivity for the diagnosis of many diseases are determined. In addition to chromatography and mass spectrograph, radioimmune and enzyme-linked immunosorbent assays, spectrophotometry, fluorometric and chemiluminescent methods were proposed, the protein matrix and tumor necrosis factor are studied, etc. In medicine, when studying gas exchange, gas analyzers are used to measure the concentration of carbon dioxide, oxygen, and nitrogen in the inhaled and the exhaled gas mixture, to study blood gases and

Semiconductor Gas Sensors of Exhaled Breath
It is important today we develop the individual metabolic profile of the patient. The equipment mentioned above is expensive and bulky, it is necessary to develop cheap, small-size and bio-safe measuring setups which can be used individually by a medical doctor and each patient elsewhere out of hospitals and specialized centers. Therefore, the use of semiconductor gas sensors for detecting the concentration of detectable gas (acetone in diabetes, for example) is widely discussed in the literature (see, for example, [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]).
Different metal oxide semiconductors for the manufacture of such sensors are proposed and investigated because they are not oxidized materials, have stable in time characteristics, and can work at its remarkable pre-heating. Determination of the concentration of chemical compounds in explosives using gas sensors will allow the diagnosis of the disease already in the early stages and will make it possible to control treatment. As was mentioned above, by the concentration of acetone and the amount of current passing through the semiconductor sensor, for example, one can judge the degree of diabetes, acute heart failure, lung cancer; hydrogen peroxide and nitric oxide--asthma and other pulmonary diseases, cancer of the digestive system; ammonia and hydrogen sulfide -hepatitis and cirrhosis; hydrogen and methane, a number of diseases of the digestive system, etc ( Diseases of the kidneys and liver (kidney failure, liver dysfunction,29 hepatic encephalopathy, renal insufficiency in nephritis, idiopathic hypertension, atherosclerosis of renal artery, toxicities and nephropathy of pregnant, toxic defeats of kidneys, paucity of the liver in jaundice, cirrhosis of the liver) Acute and chronic radiation sickness The metabolism of monoamine in the brain Uremia Swelling of brain,  [7,[9][10][11][12]14]. Note that the disease diagnosis using exhaled breath is still in the nascent stage and needs further improvement for clinic applications.

Renal Disease
The most important biomarkers of diseases in human body are nitic oxide. ammonia, acetone, hydrogen dioxide and sulphide.
Of course, a lot of information can be received from detection of other exhaled gases (   [34] which is normally exhaled and contains a variety of components from small ions to proteins and organelles, even viruses, fungi and bacteria [35][36][37]. EBC samples could be easily collected using the collection chamber cooled down the temperature of from 0 to -25°C [34,38]. After 2.5 minutes, exposure to 10-ppm hydrogen peroxide or 2 ppm triemethylene glycol vapor resulted in 99% inactivation influenza viruses on surfaces [39]. Barnes, and his colleagues at the National Heart and Lung It was also shown in Protokol [40] that inhaled nitric oxide gas (iNO) has antiviral activity against other strains of coronavirus.  [40]. To improve safety, in the present trial, iNO is administered and monitored by trained clinicians. The NO 2 will be monitored and maintained at levels of below 2 ppm. Met-Hb is continuously monitored by non-invasive CO-oximetry.

Detection of H 2 S for Diagnosing Halitosis
The degradation of S-containing amino acids in the oral cavity, upper/lower respiratory tract, and alveolar exchange with blood lead to halitosis. It is detectable as highly odorous gases with concentrations less than 1 ppm, that can be used to diagnose RH. Therefore, CuO is effective both in dry air and exhaled breath.
Liang et al. [50] reported that the CuO-loaded In 2 O 3 nanofiber sensor showed reversible H 2 S sensing characteristics above 300°C.
Doping Mo on ZnO nanowires not only increased selectivity to H 2 S but addition significantly enhanced the reversibility of the H 2 S sensing characteristics. Ag was also reported to be an effective addition. Yoneda et al. [51] provided a mini review on various techniques for the analysis of halitosis. Some other investigations of the H 2 S sensing characteristics reported in [41,[50][51][52][53].

Investigations of Metal Oxides Biomarkers Sensitive to Hydrogen, Hydrogen Dioxide, Isoprene, and Aldehides
Hydrogen sensors implemented at Yerevan State University (YSU) [53][54][55] are highly sensitive. It is important that sensors are very sensitive even at relatively high gas concentrations. Remember that the concentration of hydrogen exhaled by a healthy patient is already about 6%, and with the diseases noted above in the Table 1, this concentration is even higher. Therefore, the use of our hydrogen sensors for biomedical applications is very promising.
As for the hydrogen peroxide H 2 O 2 sensors developed at YSU [56][57][58][59], the detection of low concentrations of exhaled gas (in the range of less than one up to one hundred ppm), which is just characteristic of our sensors, is already required here. In addition, ZnO samples doped with CNTs [60,61].
The investigations of the response of metal oxide sensors to isoprene are carried out in [62]. Gaseous aldehyde breath biomarkers were proposed [63].  We developed different gas analyzers (see, for example [68]). Figure 1 shows the possibility of implementing such a acetone gas detector using a programmable board and the Arduino Nano memory [71]. Earlier, we developed also a device, which allows us to measure simultaneously three gases-methane, carbon monoxide, and hydrogen. Note also that pretreatment components such as dehumidifiers, preconcentrates, and flow sensors are very important for precise analysis. To miniaturize the system and achieve in situ diagnosis, the adsorption of analyte gases, interference gases, and moisture needs to be significantly improved.

Conclusion
One of the most important directions of modern medicine is non-invasive diagnostics of the patient, based on the analysis of exhaled air in a special device. Data on the surveillance capabilities of various diseases in the allocation of specific gases are collected.

Conflicts of Interest
The authors have no conflicts of interest to declare.