CN103202696B - Modeling method for detecting lung diseases through expiratory air on basis of aerosol - Google Patents
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Abstract
The invention relates to a modeling method for detecting lung diseases through expiratory air on the basis of aerosol. The modeling method includes the following steps: 1) building a human lung structure model; 2) enabling the human lung structure model built in the step 1) to inhale aerosol particles with fluorescent marks; 3) collecting the aerosol particles with the fluorescent marks in the step 2) through a membrane filter after the aerosol particles with the fluorescent marks are circulated in the human lung structure model; 4) performing qualitative analysis and quantitative analysis on the aerosol particles with the fluorescent marks, wherein the aerosol particles with the fluorescent marks are collected by the membrane filter; and 5) judging diseased regions and lesion extent of the lung diseases according to qualitative analysis and/or quantitative analysis results obtained in the step 4). The modeling method for detecting lung diseases through the expiratory air on the basis of the aerosol is high in feasibility and has guiding significance for clinical diagnosis.
Description
Technical field
The invention belongs to medical domain, relate to a kind of modeling method of medical diagnosis on disease, particularly relate to a kind of modeling method detecting pulmonary disease based on aerosol expired gas.
Background technology
The factors such as the physical and chemical factor caused due to atmospheric pollution, smoking, Industrial Economic Development, biotic factor suck and population ages is aging, make the sickness rate of respiratory system disease as pulmonary carcinoma, bronchial asthma in recent years obviously increase.According to the statistical number of national urbans in 2006 and the rural area top ten principal disease cause of death, respiratory system disease (not comprising pulmonary carcinoma) accounts for the 4th (13.1%) in the Death causes in city, accounts for the 3rd (16.4%) in rural area.Sickness rate and the case fatality rate of pulmonary carcinoma occupy l position in male malignancy, occupy the 2nd in women.It is very large that these statistical datas illustrate that respiratory system disease is still our people's health hazard, and it prevents and treats arduous task.But due to the complexity of respiratory system structure, make to clarify a diagnosis in early days comparatively difficulty.
But early stage clearly dyspneic reason and discovery respiratory tract neoplasms, will gain time for curing these diseases.Particularly pulmonary carcinoma early discovery and diagnosis are the keys of its treatment.Such as, if Patients with Non-small-cell Lung diagnoses its cure rate to surpass 70% when I phase, but diagnose its cure rate will lower than 25% when III phase.The traditional diagnosis method of pulmonary disease and lung tumors comprises and checks pulmonary function with spirometer, and chest x-ray develops, and CT/PET/SPET notes abnormalities the type of structure, sputum cytology and the clear and definite tumor of Lung biopsy.These diagnostic methods are totally reliable, but they have some shortcomings simultaneously: cost is high, time-consuming, need special technical staff's operation, even has some to have traumatic (bronchoscope) and radioactivity (CT/PET/SPET).
In recent years, detect pulmonary disease with expired gas gradually to come into one's own.Expired gas detection is compared with traditional method, and it has easy and noninvasive feature, therefore has in a large number about the research of expired gas biomarker.Research is had to point out that the rising of nitric oxide level in expired gas occurs relevant with asthma, the level of antioxidant is in progress relevant to COPD, cytokine occurs relevant with chemotactic factor with cystic fibrosis, and hydrogen peroxide, decane are relevant with the generation of nonsmall-cell lung cancer with isoprene.Even have some expired gas biomarkers to be applied to clinical (such as detecting nitric oxide in asthmatic patient expired gas), other be then mainly used in clinical research (such as VOC).Had been reported by the research and development detecting organic compound (VOC) diagnosing and relevant device in expired gas.Detecting the equipment of VOC, usually to have volume little, and do not have traumatic, easily grasp using and lower-price characteristic, this is significant to the efficiency improving diagnosing and other respiratory system diseases.But above-mentioned research only detects existence and the concentration of chemical substance in breath, they can not provide the diseased region or Airway Remodeling level that produce these chemical substances, and the key that these two are pulmonary carcinoma and some pulmonary disease and treat.
At present, can only by the position of the clear and definite pathological changes of Imaging Technology such as CT or PET.But this technical costs is higher and have Radio Active Hazard.More importantly, it can not carry out the treatment of targeted drug.Therefore, select a kind of method that is safer, cheaper extremely urgent.
Computational fluid dynamics (Computational Fluid Dynamics is called for short CFD) is by computer numerical value calculation and image display, to the analysis that the system including the relevant physical phenomenas such as fluid flowing and conduction of heat is done.The current world and the domestic scholar of having are studied by computational fluid dynamics method establishment model, relate generally to cardiovascular aspect, about the research of respiratory system is little, and not yet find about the research of aerosol expired gas detection pulmonary disease.
Summary of the invention
In order to solve the above-mentioned technical problem existed in background technology, the invention provides a kind of feasibility high and to clinical diagnosis there is directive significance detect the modeling method of pulmonary disease based on aerosol expired gas.
Technical solution of the present invention is: the invention provides a kind of modeling method detecting pulmonary disease based on aerosol expired gas, its special character is: said method comprising the steps of:
1) human lung's structural model is set up;
2) human lung's structural model step 1) being set up sucks with fluorescently-labeled aerosol particle;
3) step 2) in collect with membrane filter after human lung's mold cycle with fluorescently-labeled aerosol particle;
4) qualitative analysis and quantitative analysis is carried out to what obtain collected by membrane filter with fluorescently-labeled aerosol particle;
5) qualitative analysis obtained according to step 4) and/or the result of quantitative analysis judge diseased region and the lesion degree of pulmonary disease.
Above-mentioned steps 1) specific implementation be:
1.1) GAMBIT, AUTOCAD or PROE software is utilized to set up human lung's structural model;
1.2) measure the value of biofluid dynbamics material behavior and this value invested step 1.1) in human lung's structural model of setting up;
1.3) human lung's structural model is carried out to the emulation of experimental condition; Described emulation comprises geometrical constraint, constantly acting load, shock loading, temperature characterisitic, blood flow, blood pressure, thrombosis retardance and the hydrodynamic calculations condition of respiratory system.
Above-mentioned steps 1) human lung's structural model of setting up comprises the lung model with normal air flue, the lung model suffering from trachea carina tumor, suffers from the lung model of tumor of bronchus and suffer from the lung model of asthmatic bronchospasm.
Above-mentioned steps 1) human lung's structural model of setting up is two-dimension human body lung mechanics model or 3 D human body lung mechanics model.
Above-mentioned steps 2) in aerosol be the fluorescein-labeled aerosol particle of monodispersed enuatrol produced by vibrations hole monodisperse aerosol generator or the polystyrene fluorescent solutions aerosol particle produced by medical vaporizer; The particle diameter of described aerosol particle is 2-10 μm.
Above-mentioned steps 2) in make human lung's structural model suck with the suction flow velocity of fluorescently-labeled aerosol particle be 20 ~ 30L/min.
Above-mentioned steps 4) in qualitative analysis be obtain collected by step 3) carry out colorimetric with fluorescently-labeled aerosol particle, the color produced by aerosol particle concentration and brightness are analyzed.
Above-mentioned steps 4) in quantitative analysis be carry out grain count to what obtain collected by step 3) with fluorescently-labeled aerosol particle with optical microscope.
Advantage of the present invention is:
The present invention collects breath with membrane filter after utilizing the resolving inversely method of computational fluid dynamics to find that patient sucks harmless fluorescent labeling aerosol particle, can manifest a kind ofly to seem chaos, unordered pattern.But the generation of this pattern and the geometric shape of air flue are closely-related.This pattern changes along with the change of air flue geometric shape.Each bronchial aerosol fingerprint finally forms a kind of special pattern jointly with breath.Therefore, any bronchial pathological changes all can change the formation of aerosol fingerprint, thus provides foundation for diagnosing the illness.Certainly, this just by the result that simulation human airway draws, needs to verify its feasibility and effectiveness further by clinical trial.This research is intended to by contrast clinical trial and CFD analog result, further checking this check at the feasibility of clinical implementation and effectiveness, developing a kind of new pulmonary disease detection method, build the data base about human airway simultaneously, laying the foundation for carrying out correlational study further.
The present invention has the features such as noinvasive, easy to operate, "dead", low price, is applicable to the patient that can not tolerate traumatic examination and radioexmination, and part does not have the medical institutions of the checkout facilities such as CT/PET.If through clinical its effectiveness of further confirmation, can be used as the routine screening of patients with lung cancer, this brings considerable economic benefit and social benefit will to medical institutions and society.The development of medical science is closely related with development in Hi-Tech all the time." digitized virtual human " utilizes computer image technology and combines with clinical anatomy, achieve the digitized of the structure of human body from microcosmic to macroscopic view and function, visual, fully describe tissue so that the form and function of organ, finally reach the overall accurate analog of human body information, for medical science, life science and application provide technical support.Digitized virtual human is the front subject that information technology and medical science cross-synthesis grow up, and has far reaching significance to 21 century development in science and technology.
The present invention utilizes computational fluid dynamics to simulate the air flue of human body, finds that a certain size aerosol particle is at the intrabronchial flow trace of different-diameter, determines position and the degree of pathological changes by this, and it has noinvasive, the advantage such as convenient, real-time.If popularized clinically, bring major transformation will to the diagnosis and treatment of pulmonary disease.Of the present inventionly be embodied as clear and definite pulmonary disease and provide a kind of easy, quick, noinvasive and cheap new diagnostic method, be specially adapted to some and resistance toly can not receive the patient that wound inspection maybe can not accept radioexmination.Simultaneously it can provide targeted drug treat, reduces systemic drug and treats the untoward reaction brought, and increases the drug level that local patholoic change treats, and improves the cure rate of disease, to patient and society all significant.
Accompanying drawing explanation
Fig. 1 a is the lung model structural representation with normal air flue that the present invention sets up;
Fig. 1 b is the lung model structural representation suffering from trachea carina tumor that the present invention sets up;
Fig. 1 c is the lung model structural representation suffering from tumor of bronchus that the present invention sets up;
Fig. 1 d is the lung model structural representation suffering from asthmatic bronchospasm that the present invention sets up;
To be the lung model set up in Fig. 1 a form pattern schematic diagram for the aerosol of variable grain to Fig. 2 a;
To be the lung model set up in Fig. 1 b form pattern schematic diagram for the aerosol of variable grain to Fig. 2 b;
To be the lung model set up in Fig. 1 c form pattern schematic diagram for the aerosol of variable grain to Fig. 2 c;
To be the lung model set up in Fig. 1 d form pattern schematic diagram for the aerosol of variable grain to Fig. 2 d;
Breathe out when Fig. 3 is Asthma Status aerocolloidal pattern and normal time expired gas colloidal sol pattern comparison diagram;
Fig. 4 is the position view that the granule of the pulmonary lesion deposition of the lung model set up in Fig. 1 a to Fig. 1 d discharges at first.
Detailed description of the invention
Principle of the present invention is:
The present invention collects breath with membrane filter after utilizing the resolving inversely method of computational fluid dynamics to find that patient sucks harmless fluorescent labeling aerosol particle, can manifest a kind ofly to seem chaos, unordered pattern.But the generation of this pattern and the geometric shape of air flue are closely-related.This pattern changes along with the change of air flue geometric shape.Therefore, can imagine that each bronchus in air flue all can produce its distinctive pattern a kind of, aerosol fingerprint (aerosol fingerprint, AFP) can be referred to as.Each bronchial aerosol fingerprint finally forms a kind of special pattern jointly with breath.Therefore, any bronchial pathological changes all can change the formation of aerosol fingerprint, thus provides foundation for diagnosing the illness.Certainly, this just by the result that simulation human airway draws, needs to verify its feasibility and effectiveness further by clinical trial.This research is intended to by contrast clinical trial and CFD analog result, further checking this check at the feasibility of clinical implementation and effectiveness, developing a kind of new pulmonary disease detection method, build the data base about human airway simultaneously, laying the foundation for carrying out correlational study further.
Breath can point out the clue of a lot of disease.Change due to lung tumors cellular metabolism can cause the change of certain chemical substance, therefore can produce special breath, and this just can be used for detecting disease.At medical domain, fluid model can the biofluid dynbamics feature of researching human body better.Human body has very complicated structure, and utilize GAMBIT, AUTOCAD, the modeling function of the softwares such as PROE, two dimension can be set up, 3 D human body structural model, and the biofluid dynbamics material behavior measured by hydrodynamic methods is invested this model, set up in a computer virtual " experimental specimen ", then experiment condition emulation (geometrical constraint is carried out to model, constantly acting load, shock loading, temperature characterisitic etc.), simulate blood flows, blood pressure, thrombosis blocks, the hydrodynamic calculations conditions such as respiratory system, this virtual objects and the similar hydrodynamics index of experimental specimen can be obtained by solving, the blood flow rate of any part (comprising aneurysm etc.) of such as object and blood pressure, internal energy variations in temperature, the situations of change such as limiting damage.CFD research has the incomparable advantage of experimental technique: it can produce numerous various specimen as required, same specimen can load many times or combine and can not be damaged in virtual computing, and specimen also can carry out revising to simulate any pathological state.
Have in a large number about the research of expired gas biomarker at present, the nitric oxide production level in asthmatic patient expired gas that detects has been applied to clinical, significant in Diagnosis and differential diaggnosis asthma.In detection of lung cancer patient expired gas, VOC is applied to clinical research.But can not specify diseased region and degree because existing expired gas detects, its clinical practice is subject to a definite limitation.Can predict, if aerosol expired gas detect be applied to clinical will give patient and society bring huge Social benefit and economic benefit.
In order to the feasibility of this method is described, the present invention utilizes computational fluid dynamics method to simulate from oral cavity to a 6th grade of bronchial desirable lung model.One has 4 models, is normal air flue (ModelA, Fig. 1 a), trachea carina tumor (Model B), tumor of bronchus (Model C), asthmatic bronchospasm (Model D) (Fig. 1 b-Fig. 1 d) respectively.The details of 4 kinds of models are in table 1.Different air flue geometry form can produce different aerosol exhalation fingerprints, and key is the internal relation understood between the two.Illustrate the lung model of various various disease feature in FIG: wherein Fig. 1 a is the normal air flue of Model A; Fig. 1 b is ModelB trachea carina tumor, and Fig. 1 c is Model C left bronchus tumor, and Fig. 1 d is the serious bronchospasm of Model D (asthma).Trachea is classified to the 6th grade, comprises 23 branches.
The feature of the different air flue model of table 1.
In order to Simulated gas colloidal sol fingerprint detection, aerocolloidal suction and exhalation are carried out all at steady state.Be recorded in buccal during exhalation.By computational fluid dynamics simulated respiration air-flow and aerocolloidal transmission.The expired gas colloidal sol pattern of 4 kinds of models has significant difference (see Fig. 2 a-Fig. 2 d).Fig. 2 is buccal expired gas colloidal sol pattern, and wherein Fig. 2 a is normal, and Fig. 2 b is bronchial enlargement tumor, and Fig. 2 c is left bronchus tumor and Fig. 2 d is asthma.There is the granule of 3 kinds of sizes: 1 μm, 5 μm and 10 μm.Expired gas colloidal sol pattern is the fingerprint of air passage structure, therefore can be used to the position of accurately locating abnormality.Expired gas colloidal sol pattern is difference (being similar to finger) with the change in size of Inhaled Aerosol granule, and this also can be used to position and the period of inferring lung tumors.
More significantly, each model all has its specific expired gas colloidal sol pattern, and this can help the position and the scope that judge pathological changes.For any one model, although the aerosol particle of different size (0.4 – 5 μm) pattern changes, but has similarity.Such as, the expired gas colloidal sol pattern of Model D have in its upper left corner one crescent, this and other 3 models are obviously different, but the aerosol particle of all sizes of this model has this similar pattern.Because Model D simulates bronchioles spasm, therefore the appearance hint bronchioles spasm of this figure exists.This observation confirms that expired gas colloidal sol pattern is a kind of hypothesis of the aerosol fingerprint relevant to lung mechanics.
This hypothesis can further by only detecting that aerosol particle is verified from diseased region.Such as, two bronchioles spasm (see Fig. 3) are had in Medel D.The clear-cut of red granules, and the indicator that can be used as Asthma Status.Finally, can also be used to the concrete position of the location assessment airway spasm as disease.Fig. 3 is Asthma Status and the comparing of expired gas colloidal sol pattern time normal.Red granules in Asthma Status expired gas colloidal sol pattern is from the bronchioles of two spasm.The granule of these colors change can be used to the level to pulmonary disease location and assessment airway spasm.
After the position determining pathological changes and the order of severity, according to the degree of pathological changes, drug dose can accurately be sent to affected part bronchus.About targeted drug treatment, it is crucial that the position that clear and definite medicine arrives.In order to this problem is described, first at buccal release aerosol particle, follow the trail of at the granule of pulmonary deposition according to its regioselectivity in buccal release.Fig. 4 shows the off-position of lung lesions deposited particles.In theory, if at these positions release pharmaceutical aerosol granule, all granules all can return to the position of its pathological changes and be deposited on there, which achieves targeted drug treatment.Be deposited on the aerosol particle of privileged sites all from clear and definite bronchus.Meanwhile, because left and right is bronchial asymmetric, bronchial enlargement tumor model off-position also seems asymmetric.
The lung tissue of human body be from main bronchus gradually branch attenuate and form a complex organ of alveolar.Such as, main bronchioles diameter only 1mm, terminal bronchiole is 0.5mm or thinner only, respiratory bronchioles diameter only 0.2mm.And ill lung tissue structure is more complicated.Whether aerosol expired gas detects can obtain similar result of study, and the feasibility of its manipulation check needs clinical trial to verify further on human body.
Plan chooses 10 patients with lung cancer clinically, 10 asthmatic patients, and 10 normal persons carry out contrast verification.The inclusion criteria of patients with lung cancer: 1) meet the diagnostic criteria in Ministry of Public Health pulmonary carcinoma practice guidelines (2011); 2) find for the first time, previously foundation-free disease, in apneumia, transfer, does not perform an operation and chemicotherapy; Asthmatic patient inclusion criteria: 1) meet the diagnostic criteria in prevention and control of bronchial asthma guide (2008); 2) without merging pulmonary heart disease, respiratory failure.The inclusion criteria of normal person: 1) previously without any underlying diseases; 2) coherence check can be tolerated.Through Ethics Committee of Affiliated Hospital of Xi'an Medical University examination and approval, all devices and reagent harmless.All patients (except normal person) all need to be in hospital, signature Informed Consent Form, and record the general datas such as the Diagnostic Time of its disease, treatment situation and physical examination, and patients with lung cancer need record TNM by stages.
Pulmonary carcinoma and asthmatic patient all need to carry out Thoracic CT scan, and everyone imaging data is generated aerosol exhalation pattern by computer program simulation.Normal person does not require to carry out CT scan.All personnel carries out aerosol atomizing suction detection afterwards, and concrete grammar is as follows:
1) Inhaled Aerosol granule: allow experimenter's calmness suck the aerosol particle produced by vibrations hole monodisperse aerosol generator (VOAG, Model3050, TSI, Inc St.Paul, MN).It will produce the fluorescein-labeled aerosol of monodispersed enuatrol (having confirmed harmless), diameter 2-10 μm, also need a pressurizing tank to provide lasting, stable liquid solution simultaneously.The system of this improvement can continue a few hours generation aerosol particle.In addition, also need a grain spectrometer (TSI, Inc), be used for monitoring and regulating aerosol particle size.If need aerosol particle diameter <2 μm, produce polystyrene fluorescent solutions aerosol (Duke Scientific, Palo Alto, CA) with a medical vaporizer (Hospitak, Lindenhurst, NY).Flow velocity is arranged on 20 ~ 30L/min, and this is adult's seat and breathing flow velocity during slight motion substantially.
2) breath is collected: after tranquil Inhaled Aerosol, advise experimenter's normal respiration.Breath is collected at buccal membrane filter.When gas is breathed out, little microgranule is by the hole of membrane filter, and the surface of membrane filter then stayed by large microgranule.In addition, also need the adnexa that filter is sampled: ACCU-CAP tape inserts adapter, tank prover, boxlike is blank, holds filter box, filter support, transport adnexa filter, helmet adapter, contraction bands, pipe and spider.
3) aerosol breath is analyzed: by two kinds of methods analyst results, quantitative and qualitative analysis.
Qualitative: different colors and brightness to be produced according to the concentration of aerosol particle with fluorescein imaging colorimetric aerosol.
Quantitative: to carry out grain count with optical microscope (Optiphot-66, Nikon, Tokyo, Japan).
Claims (4)
1. detect a modeling method for pulmonary disease based on aerosol expired gas, it is characterized in that: said method comprising the steps of:
1) human lung's structural model is set up; Described human lung's structural model comprises the lung model with normal air flue, the lung model suffering from trachea carina tumor, suffers from the lung model of tumor of bronchus and suffer from the lung model of asthmatic bronchospasm; The mode of specifically setting up of described human lung's structural model is:
1.1) GAMBIT, AUTOCAD or PROE software is utilized to set up human lung's structural model;
1.2) measure the value of biofluid dynbamics characteristic and give step 1.1 by this value) in human lung's structural model of setting up;
1.3) human lung's structural model is carried out to the emulation of experimental condition; Described emulation comprises geometrical constraint, constantly acting load, shock loading, temperature characterisitic, blood flow, blood pressure, thrombosis retardance and the hydrodynamic calculations condition of respiratory system;
2) step 1 is made) human lung's structural model of setting up sucks with fluorescently-labeled aerosol particle;
3) step 2) in collect with membrane filter after human lung's mold cycle with fluorescently-labeled aerosol particle;
4) qualitative analysis and quantitative analysis is carried out to what obtain collected by membrane filter with fluorescently-labeled aerosol particle; Described qualitative analysis is to step 3) collected by obtain carry out colorimetric with fluorescently-labeled aerosol particle, the color produced by aerosol particle concentration and brightness are analyzed; Described quantitative analysis is to step 3 with optical microscope) collected by obtain carry out grain count with fluorescently-labeled aerosol particle;
5) according to step 4) the result determining step 1 of the qualitative analysis that obtains and/or quantitative analysis) in the diseased region of pulmonary disease and lesion degree in human lung's structural model of setting up.
2. according to claim 1ly detecting the modeling method of pulmonary disease based on aerosol expired gas, it is characterized in that: described step 1) human lung's structural model of setting up is two-dimension human body lung mechanics model or 3 D human body lung mechanics model.
3. according to claim 1 and 2ly detect the modeling method of pulmonary disease based on aerosol expired gas, it is characterized in that: described step 2) in aerosol particle be the fluorescein-labeled aerosol particle of monodispersed enuatrol produced by vibrations hole monodisperse aerosol generator or the polystyrene fluorescent solutions aerosol particle produced by medical vaporizer; The particle diameter of described aerosol particle is 2-10 μm.
4. according to claim 3ly detect the modeling method of pulmonary disease based on aerosol expired gas, it is characterized in that: described step 2) in human lung's structural model is sucked with fluorescently-labeled aerosol particle suction flow velocity be 20 ~ 30L/min.
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| US20180296124A1 (en) * | 2015-10-07 | 2018-10-18 | Koninklijke Philips N.V. | Device, sysem and method for determining a respiratory feature of a subject based on a breathing gas |
| CN109584695A (en) * | 2018-10-19 | 2019-04-05 | 清华大学合肥公共安全研究院 | Smoke settlement simulation system in a kind of respiratory system |
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