Portable traditional Chinese medicine olfactory diagnosis instrument

Abstract

The utility model discloses a portable traditional Chinese medicine olfactory diagnosis instrument, which comprises a sample collection device, a gas enrichment device, a mass spectrometer, a data processor and a display, the mass spectrometer is sequentially connected with the data processor and the display, the gas enrichment device is test paper with an enrichment reagent encapsulating nano-metal particles, the enrichment efficiency is effectively improved, and the detection accuracy is improved. Therefore, the detection sensitivity and accuracy of the mass spectrometer are improved; the device is provided with the ion trap mass spectrometer, has the characteristics of high detection speed, high resolution and high sensitivity, and has performance advantages in qualitative and trace analysis aspects; and due to small volume and strong portability, the device can be conveniently integrated into portable or field detection equipment, can be used for auxiliary diagnosis of heart failure and asthma, and also has great clinical application value in the aspects of disease evolution and disease prognosis evaluation.

Description

TECHNICAL FIELD

[0001] The utility model relates to the field of clinical diagnosis instrument, specifically, relate to a portable traditional chinese medicine smell diagnosis appearance. BACKGROUND

[0002] Traditional Chinese medicine differentiation is an important basis for doctors to prescribe medicine, and the four diagnostic methods of observation, listening, interrogation and palpation are the core method of basic diagnosis of traditional Chinese medicine. The "listening" in the four diagnostic methods includes "auscultation" by listening to sound and "smell diagnosis" by smelling odor, which is a method of understanding health status and diagnosing diseases by listening to sound and smelling odor. Among them, "smell diagnosis" refers to a method of diagnosing diseases by distinguishing between patient body odor and room odor.

[0003] Ancient physicians have a long history of using olfactory diagnosis to guide clinical practice. The earliest record of "olfactory diagnosis" may be found in the *Huangdi Neijing Suwen* (Yellow Emperor's Inner Classic - Basic Questions) section on "Golden Chamber True Words," which mentions: "The liver... when diseased in the tendons, has a foul odor; the heart... when diseased in the vessels, has a burnt odor; the spleen... when diseased in the flesh, has a fragrant odor; the lungs... when diseased in the skin and hair, has a fishy odor; the kidneys... when diseased in the bones, has a putrid odor," thus introducing the concept of "five odors." The *Zhouli* (Rites of Zhou) records that during the Western Zhou period, "the physician was in charge of treating the diseases of all people... using the five odors, five sounds, and five colors to judge their life and death," indicating that doctors at that time could already determine a patient's life or death based on their odor, voice, and complexion. The *Nan Jing* (Classic of Difficult Issues), in its fourteenth chapter, states: "The liver is green, and its odor is rancid... The heart is red, and its odor is burnt... The spleen is yellow, and its odor is fragrant... The lungs are white, and their odor is fishy... The kidneys are black, and their odor is putrid." The *Nan Jing*, in its forty-ninth chapter, states: "The heart governs odor; when it enters the body, it produces a burnt odor; when it enters the spleen, it produces a fragrant odor; when it enters the liver, it produces a rancid odor; when it enters the kidneys, it produces a putrid odor; when it enters the lungs, it produces a fishy odor. Therefore, it is known that heart disease caused by heatstroke will cause an aversion to the burnt odor." These descriptions of the "color" and "odor" of the five internal organs respectively establish the use of smell as a diagnostic method. During the Qin and Han dynasties, traditional Chinese medicine began to flourish, and people gradually understood diseases and accumulated clinical experience. The *Jin Gui Yao Lue* (Essential Prescriptions of the Golden Chamber), in its section on pulmonary atrophy, pulmonary abscess, cough, and shortness of breath, describes the odor as "turbid saliva and fishy odor," indicating heat accumulation and toxin buildup in the lungs, leading to blood deterioration and flesh decay, resulting in abscesses and pus. During the Jin, Tang, Song, Jin, and Yuan dynasties, traditional Chinese medicine theory gradually formed a complete system, and the increased emphasis on auscultation and olfaction led to its development. In the *Pulse Classic* by Wang Shuhe of the Jin Dynasty, it is mentioned that Bian Que's methods for predicting critical illness included "patients with a corpse-like odor are incurable" and "febrile diseases...numbness and odor indicate latent poison damaging the lungs," suggesting that the appearance of foul odors in jaundice patients was a sign of impending death due to the exhaustion of the lungs and spleen. By the Ming and Qing Dynasties, the use of olfactory diagnosis became increasingly frequent and gradually developed into a theoretical system. In his *Expanded Treatise on Epidemic Diseases*, Dai Tianzhang of the Qing Dynasty proposed five differentiations for diagnosing typhoid fever, the first being the differentiation of qi: "Wind and cold qi retreat from the outside to the inside; the patient will not have a foul odor. If a foul odor is present, it will only appear after several days when the condition transforms into a Yangming bowel syndrome, and will only produce a putrid odor, not a corpse-like odor." The importance of olfactory diagnosis is evident in the vast history of traditional Chinese medicine diagnosis. Traditional Chinese medicine believes that various odors in the human body are produced during the physiological activities and pathological changes of the internal organs. In disease conditions, due to the invasion of pathogenic factors, abnormal qi and blood circulation, and dysfunction of the internal organs, the elimination of impurities is hindered, producing putrid odors, which can manifest as abnormal odors in breath, body odor, secretions, and excretions.

[0004] However, traditional Chinese medicine olfactory diagnosis has many limitations. For example, traditional Chinese medicine olfactory diagnosis is mainly based on the subjective smell of doctors, and lacks objective basis and standards. Studies have found that there are individual differences in human olfaction, and there may be substances that are more sensitive to their own olfaction. If people live in a certain smell for a long time, their sensitivity to the identification of that smell will also decrease. Moreover, human olfaction is also affected by psychological factors. This makes the accuracy and reliability of olfactory diagnosis, as a highly subjective diagnostic method, questionable, and the results are easily affected by various factors. In today's medical system, doctors need to wear masks when they see patients, which to some extent hinders doctors' identification of patients' smell.

[0005] In fact, olfactory diagnosis has the advantages of non-invasive and painless diagnosis, and is a very potential diagnostic method. In recent years, the continuous development of medical engineering and multidisciplinary integration has promoted Chinese medicine to gradually cross to precise, efficient and personalized medicine, and Chinese medicine olfactory diagnosis has entered a new era of 'digitalization' development. Therefore, the development of modern medical instruments for olfactory diagnosis is an effective way to promote the objective and digital innovation and development of Chinese medicine olfactory diagnosis.

[0006] Olfactory samples, such as human breath (i.e., exhaled breath), contain a large number of volatile organic compounds (VOCs), and most of these VOCs are involved in the internal metabolic process of human tissues. When the body has pathological conditions, the types and quantities of VOCs will change significantly, showing great potential in clinical disease screening.

[0007] For exhaled breath analysis, some scholars in the field have used a variety of modern scientific instruments for exhaled breath analysis, such as spectroscopy, chromatography, electronic nose, mass spectrometry, etc. Spectroscopy is a method of identifying substances and determining their chemical composition and relative content by measuring the wavelength and intensity of emitted, absorbed or scattered radiation produced by quantumized energy level transitions within the substance when it interacts with radiation energy. It mainly includes Fourier transform infrared spectroscopy (FTIR), tunable diode laser absorption spectroscopy (TDLAS), cavity ring-down spectroscopy (CRDS), photo acoustic spectroscopy (PAS), etc. However, spectroscopy has the problems of high cost, large size, complex operation, susceptibility to water vapor interference in exhaled breath, and difficulty in covering the dynamic range of all volatile organic compounds (VOCs), which limits its widespread application in clinical and on-site rapid screening.

[0008] Electronic nose, also known as artificial olfactory system, is designed to mimic the biological olfactory system. It consists of three parts: gas sensor array, signal processing circuit and pattern recognition unit. It can provide the overall information of volatile components in the sample, i.e. obtain the simulated olfactory "fingerprint". However, the electronic nose technology cannot identify the specific information of individual volatile components, nor can it explore the biomarkers related to specific diseases.

[0009] Mass spectrometry is mainly divided into two types: mass spectrometry coupled with chromatography, which usually requires complex sample pretreatment, including gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS) and capillary electrophoresis-mass spectrometry (CE-MS) etc.; and direct analysis mass spectrometry, including proton-transfer reaction mass spectrometry (PTR-MS), selected-ion flow-tube mass spectrometry (SIFT-MS), secondary electro-spray ionization mass spectrometry (SESI-MS), extractive electrospray ionization (EESI-MS) etc. Mass spectrometry technology has significant advantages in exhaled breath analysis compared to other technologies, including high sensitivity and specificity, wide detectable range, powerful structural resolution ability, rapid analysis and high throughput, combination with other technologies, direct analysis without derivatization, and dynamic monitoring ability. These characteristics make mass spectrometry technology an ideal tool for complex biological sample analysis and biomarker discovery. Traditional large-scale mass spectrometry equipment requires a clean experimental environment and is often operated by experienced professionals, which cannot be applied to on-site direct analysis. Portable mass spectrometers have high performance while being portable, easy to operate and low in power consumption, which can reduce costs, simplify operation procedures, promote point-of-care testing and personalized medicine, and meet the needs of modern medicine for efficient, convenient and accurate diagnostic tools.

[0010] The analysis of olfactory diagnosis samples often requires the enrichment of VOCs in them. This is because the concentration of VOCs in olfactory diagnosis samples is extremely low, about 10 -12 ~ 10-9 Even if the most sensitive instrument category, mass spectrometry, is used for analysis, the sample needs to be enriched for pretreatment to improve the concentration of VOCs to be tested. The conventional sample pretreatment method is mainly solid-phase microextraction (SPME). SPME has become one of the most widely used sample pretreatment techniques due to its simple operation, rapid and effective, and easy automation. Its principle is to coat a millimeter-level columnar fiber with a micron-level adsorption material. Since the adsorption coating is thin, the analyte can quickly reach adsorption equilibrium, thereby reducing the time for sample enrichment. However, the types of commercially available SPME coatings are limited, and it is difficult to cover all target analytes, especially for low-concentration compounds in complex matrices, the selectivity is poor. Moreover, the coating has a limited service life and may wear and fall off during use, resulting in reduced stability and repeatability of the analysis results. Therefore, a mass spectrometry ion source with VOCs enrichment function is needed as the sample inlet component of the olfactometry instrument based on mass spectrometry technology.

[0011] According to literature reports, many studies have explored the correlation between VOCs and various diseases, such as heart failure, asthma, diabetes, lung cancer, and colorectal cancer. Aldehyde ketone compounds are frequently used as biomarkers for diseases due to their specificity. Among them, heart failure (HF), hereinafter referred to as heart failure, is a multifactorial cardiovascular disease characterized by impaired cardiac pumping function, leading to insufficient blood supply and oxygen supply to organs. Heart failure is classified into the categories of "palpitation", "asthma", "cardiac distension", "cardiac edema", and "edema" in traditional Chinese medicine diagnosis. Asthma (Asthma), hereinafter referred to as asthma, is an inflammatory disease characterized by recurrent wheezing, chest tightness, or cough as the main symptoms, and chronic inflammation and hyperresponsiveness of the airway are its pathological features. Traditional Chinese medicine believes that the disease is caused by the accumulation of phlegm in the lungs, combined with external factors, diet, emotions, and overwork, leading to qi stagnation and phlegm obstruction, airway spasm and stenosis. The following takes the early diagnosis of heart failure and the differentiation of TCM syndromes of asthma based on exhaled breath olfactometry analysis as an example to illustrate the application of the TCM olfactometry instrument in traditional Chinese medicine diagnosis, syndrome differentiation, and other clinical practices. Practical new type content

[0012] To solve the problems in the prior art, the utility model provides a portable traditional Chinese medicine olfactometry instrument, which solves the problems of low content of volatile organic compounds VOCs in the olfactometry sample, low sensitivity of traditional analysis methods, long analysis time, and limited site.

[0013] To achieve the foregoing purposes, the utility model adopts the technical scheme of:

[0014] A traditional Chinese medicine smell diagnosis instrument, comprising: a sample collection device, a gas enrichment device, a mass spectrometer, a data processor and a display, the mass spectrometer is sequentially connected with the data processor and the display, the gas enrichment device is a triangular enrichment paper, smell diagnosis sample gas is collected and stored through the collection device, is enriched through the gas enrichment device, is washed into the mass spectrometer with an eluent during detection, the data processor pre-processes original data extracted from a VOCs mass spectrum obtained from the smell diagnosis sample, and inputs the original data into an OPLS-DA model, so that the smell diagnosis sample is classified, and corresponding results are output.

[0015] The sample collection device comprises a gas sample collection device, a liquid sample collection device and a solid sample collection device.

[0016] The gas collection device comprises a disposable nozzle, an air inlet valve, a gas bag and an air outlet valve connected in sequence.

[0017] The liquid sample collection device comprises a centrifugal tube, a sealed glass bottle with a bottle cap and a partition pad.

[0018] The solid sample collection device comprises a sterile toilet box and a sealed glass bottle with a bottle cap and a partition pad.

[0019] The enrichment paper is a test paper in which reagent nano metal particles are encapsulated.

[0020] The enrichment reagent is p-mercaptobenzoyl hydrazine.

[0021] The nano metal particles are nano silver particles.

[0022] The eluent is a methanol solution of 1-dodecanethiol.

[0023] The mass spectrometer is an ion trap mass spectrometer.

[0024] Compared with the prior art, the beneficial effects of the utility model lie in that:

[0025] 1. The gas enrichment device in the traditional Chinese medicine smell diagnosis instrument of the utility model significantly improves the concentration of target compounds in the sample, effectively improves the enrichment efficiency, shortens the enrichment time, thereby improves the detection sensitivity and accuracy of the mass spectrometer, has good stability and reproducibility, and has low material cost, and is economic and easy to implement.

[0026] 2. The traditional Chinese medicine smell diagnosis instrument of the utility model is equipped with an ion trap mass spectrometer, has the characteristics of fast detection speed, high resolution and high sensitivity, has performance advantages in qualitative and trace analysis, and is small in size and strong in portability, is convenient to integrate into portable or on-site detection equipment, can be used for auxiliary diagnosis of heart failure and asthma, and has great clinical application value in disease evolution and disease prognosis evaluation. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 It is a structure schematic view of the portable traditional Chinese medicine smell diagnosis instrument device of the embodiment of the present application;

[0028] Figure 1 The middle marks are respectively: 1-enrichment device, 2-portable ion trap mass spectrometer, 3-data processor display, 4-high voltage power supply, 5-conductor, 6-sample inlet tube, 7-ion funnel, 8-ion trap, 9-radiating fan, 10-circuit mainboard;

[0029] Figure 2 It is a gas sample collection device schematic view of the embodiment of the present application;

[0030] Figure 2 The middle marks are respectively: 11-gas bag, 12-disposable blowing nozzle, 13-gas inlet valve, 14-gas outlet valve;

[0031] Figure 3 It is a non-gas sample collection device schematic view of the embodiment of the present application;

[0032] Figure 3 The middle marks are respectively: 15-centrifugal tube containing sample, 16-glass bottle (bottle cap with gasket).

[0033] Figure 4 It is an analysis process schematic view of the portable traditional Chinese medicine smell diagnosis instrument of the embodiment of the present application;

[0034] Figure 5 It is the result of detecting 1ppm benzaldehyde gas under multiple reaction monitoring (MRM) mode by using enrichment paper;

[0035] Figure 6 It is the result of detecting 0.1ppt benzaldehyde gas under MRM mode by using enrichment paper;

[0036] Figure 7 It is a standard curve for quantitative analysis of formaldehyde gas;

[0037] Figure 8 A is the OPLS-DA model score plot of exhaled gas of heart failure patients and healthy people; B is the OPLS-DA model score plot of exhaled gas of asthma patients with excess syndrome and deficiency syndrome. DETAILED DESCRIPTION

[0038] The technical solution of this utility model will now be clearly and completely described. Obviously, the described embodiments are only some, not all, of the embodiments of this utility model. The components of the embodiments of this utility model described and shown in the accompanying drawings can be arranged and designed in various different configurations. All other embodiments obtained by those skilled in the art based on the embodiments of this utility model without inventive effort are within the scope of protection of this utility model.

[0039] The device diagram of the portable TCM olfactory diagnostic instrument according to an embodiment of this utility model is shown below. Figure 1 As shown, the instrument includes: a sample collection device, a gas enrichment device 1, an ion trap mass spectrometer 2, a data processor, and a display 3; the ion trap mass spectrometer 2, the data processor, and the display 3 are connected in sequence.

[0040] like Figure 2 As shown, the gas sample collection device is used to collect and store exhaled gas, including a disposable mouthpiece 12, an inlet valve 13, an air bag 11, and an outlet valve 14 connected in sequence.

[0041] like Figure 3 As shown, the liquid sample collection device is used to collect gases emitted from urine and includes a centrifuge tube 15 and a sealable glass bottle 17 with a septum cap; the solid sample collection device is used to collect gases emitted from feces and includes a sterile stool container 16 and a sealable glass bottle 17 with a septum cap.

[0042] Exhaled breath sampling requirements: Subjects must fast for at least 8 hours before sampling. Sampling time is 8:00 AM. Before sampling, subjects should sit quietly in the room for 10-15 minutes and rinse their mouths with water. Subjects should open the inlet valve 13 and the outlet valve 14, take three deep breaths, and then take two calm breaths. After that, blow air into the air for 10 seconds, then hold the disposable mouthpiece 12 in their mouth and blow air into the air bag until they feel slight resistance in their lungs. Then, close the outlet valve and the inlet valve. Subjects must not breathe during exhalation.

[0043] Urine sampling requirements: Subjects must fast for at least 8 hours before sampling and abstain from food and water after waking up the following morning. Collect fresh midstream urine in the morning and seal it in centrifuge tube 15. Female subjects should avoid collecting urine samples during their menstrual period. Transfer the urine from the centrifuge tube to a sealable glass bottle 17 with a septum cap for testing.

[0044] Stool sampling requirements: Subjects should maintain a normal diet before sampling, avoiding overeating, spicy foods, and foods that are difficult to digest. Take a small amount of fresh stool (approximately the size of a thumb) and place it in a dry, clean, and covered sterile stool container 16. The sample should not contain urine, and should also avoid mixing with other liquids from bedpans or toilets. Transfer a small amount of stool from the container to a sealable glass bottle 17 with a septum cap for testing.

[0045] Referring to Figure 4 As shown in the utility model in the application of smell diagnosis sample collection and enrichment process.

[0046] Gas enrichment device 1 is to mercaptobenzoyl hydrazine encapsulated nanosilver particles chromatographic paper. Chromatographic paper is cut into a triangle with a height of 2cm and a base of 1.5cm, because the top angle of the triangle can make the liquid more easily gathered and form a relatively stable electrospray tip, which is conducive to the atomization and ionization process of the sample solution, and facilitates subsequent mass spectrometric detection. The structure of mercaptobenzoyl hydrazine is shown below:

[0047]

[0048] Gas enrichment device 1 is used for enriching smell diagnosis samples, including human exhaled air, sweat, urine, feces and other odors. Due to the group characteristics of the enrichment reagent, it can specifically bind with aldehyde ketone compounds in the smell diagnosis sample to improve the concentration of aldehyde ketone compounds in the sample.

[0049] During detection, 10μL of a series of concentrations of benzaldehyde methanol solution is dropped into a 50mL centrifuge tube, and placed in a 37℃ incubator for 30min to obtain benzaldehyde gas as a sample for quantitative analysis. The exhaled air sample does not need this step, and the urine and feces samples are moved into a sealable glass bottle with a bottle cap with a spacer and incubated under the same conditions. 10μL of methanol is used to pre-wet the dried enrichment paper, which is placed in a clean glass syringe. 20mL of exhaled air is extracted from the gas bag of the sample to be tested using the syringe, and the urine and feces samples are extracted from the bottle cap with a spacer in the sealable glass bottle. Incubate in a constant temperature incubator at 60℃ for 10min. Take out the test paper and clamp it in a copper clamp 5mm in front of the sample inlet of the olfactometry instrument. Add 1-dodecanethiol methanol solution (25μL, 0.02M) to the tail end of the test paper as an eluent. A direct current voltage of +3-5kV is connected to the copper clamp for detection, preferably 3.5kV.

[0050] Ion trap mass spectrometer, used for detecting samples concentrated by enrichment paper. Figure 5 The results of detecting 1ppm benzaldehyde gas using enrichment paper in MRM mode, the m / z of the product precursor ion after reaction is 257.1, and the m / z of the fragment ion is 179. It can be seen that the enrichment paper can enrich aldehyde ketone compounds and be detected by the olfactometry instrument. Figure 6 The results of detecting 0.1ppt benzaldehyde gas using enrichment paper in MRM mode, the characteristic fragment ion 179.0 can still be seen. It shows that the detection limit of the olfactometry instrument is lower than 0.1ppt, and the sensitivity is high. Figure 7 The standard curve for quantitative analysis of benzaldehyde gas, the linear range is 2ppt to 1ppm, R 2=0.9986, indicating that there is a stable linear relationship, the result is accurate and reliable. The test paper enriched with the exhaled air sample is detected by the same method, and the results of the two groups are input into the data processor 3.

[0051] The data processor and display 3 pre-process the obtained mass spectrum data and input into the established OPLS-DA model for classification. The orthogonal partial least squares discriminant analysis (OPLS-DA) is a multivariate statistical analysis method, mainly used for data classification and pattern recognition, and has a wide application in the fields of chemistry, biology, medicine and environmental science. It is based on the combination of partial least squares and orthogonal projection, and distinguishes sample categories through dimension reduction and denoising, and is widely used in high-dimensional data analysis such as metabolomics and transcriptomics, and is a commonly used method in current data classification tasks. Figure 8 A indicates the classification results of exhaled air of heart failure patients (HF) and healthy people (HC), and B indicates the classification results of exhaled air of asthma patients (S) and asthma patients (X). R 2 and Q 2 respectively indicate the explanation ability and prediction ability of the model, and the R 2 Y and Q 2 of the two OPLS-DA models established in the utility model are all >0.8, indicating that the diagnostic performance and prediction performance of the model are both good. The sample points of the two groups of samples are respectively gathered in different quadrants, indicating that the distinguishability and aggregation are good, proving that there is a certain difference in the exhalation components between the groups.

[0052] The above examples are only exemplary and do not constitute any limitation on the scope of the utility model. Those skilled in the art should understand that the details and forms of the technical solutions of the utility model can be modified or replaced without deviating from the spirit and scope of the utility model, but these modifications and replacements all fall within the protection scope of the utility model.

Claims

1. A portable traditional Chinese medicine smell diagnosis instrument, characterized in that, It comprises a sample collection device, a gas enrichment device (1), a mass spectrometer (2), a data processor and a display (3), the mass spectrometer (2) is sequentially connected with the data processor and the display (3), the gas enrichment device (1) is a triangular enrichment paper, the enrichment paper is a test paper with enrichment reagent encapsulating nano metal particles, a smelling sample gas is collected and stored through the sample collection device, enriched through the gas enrichment device (1), and enters the mass spectrometer (2) through elution with an eluent during detection, the data processor pre-processes original data extracted from a VOCs mass spectrum of the smelling sample, inputs the original data into an OPLS-DA model, classifies the smelling sample, and outputs corresponding results. The sample collection device comprises a gas sample collection device, a liquid sample collection device and a solid sample collection device.

2. The portable traditional Chinese medicine olfactory diagnosis instrument according to claim 1, characterized in that: The gas sample collection device comprises a disposable nozzle (12), an air inlet valve (13), a gas bag (11) and an air outlet valve (14) which are sequentially connected.

3. The portable traditional Chinese medicine olfactory diagnosis instrument according to claim 2, characterized in that: The liquid sample collection device comprises a centrifugal tube (15) and a sealed glass bottle (17) with a bottle cap and a partition pad.

4. The portable traditional Chinese medicine olfactory diagnosis apparatus according to claim 2, characterized in that: The solid sample collection device comprises a sterile toilet box (16) and a sealed glass bottle (17) with a bottle cap and a partition pad.

5. The portable traditional Chinese medicine olfactory diagnosis apparatus according to claim 2, characterized in that: The enrichment reagent is p-mercaptobenzoyl hydrazine.

6. The portable traditional Chinese medicine olfactory diagnosis apparatus according to claim 1, characterized in that: The nano metal particles are nano silver particles.

7. The portable traditional Chinese medicine olfactory diagnosis instrument according to claim 1, characterized in that: The eluent is a methanol solution of 1-dodecanethiol.

8. The portable traditional Chinese medicine olfactory diagnosis apparatus according to claim 1, characterized in that: The mass spectrometer is an ion trap mass spectrometer.

9. The portable traditional Chinese medicine olfactory diagnosis apparatus according to claim 1, characterized in that: ​

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