CN103202696A - 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, relate in particular to a kind of modeling method that detects pulmonary disease based on the aerosol expired gas.
Background technology
Because factors such as the physical and chemical factor that atmospheric pollution, smoking, Industrial Economic Development cause, biotic factor suck and population ages is aging, the sickness rate of respiratory system disease in recent years such as pulmonary carcinoma, bronchial asthma is obviously increased.According to the statistical number of national part city 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 dead cause of disease in city, account in the rural area the 3rd (16.4%).The sickness rate of pulmonary carcinoma and case fatality rate occupy the l position in male's malignant tumor, occupy the 2nd in the women.These statistical data explanation respiratory system diseases are still very big to China's people's health hazard, it prevents and treats the task arduousness.But because the complexity of respiratory system structure makes the comparatively difficulty of clarifying a diagnosis in early days.
Yet early stage clear and definite 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.For example, if the nonsmall-cell lung cancer patient diagnoses its cure rate to surpass 70% in I during the phase, but diagnose its cure rate will be lower than 25% during the phase in III.The traditional diagnosis method of pulmonary disease and lung tumors comprises with spirometer and checks pulmonary function, and chest x-ray develops, CT/PET/SPET note abnormalities structure, sputum cytology and the clear and definite tumor type of lung tissue biopsy.These diagnostic methods totally are reliably, but they have some shortcomings simultaneously: cost height, technical staff time-consuming, need be special operate, even have some to have traumatic (bronchoscope) and radioactivity (CT/PET/SPET).
In recent years, detecting pulmonary disease with expired gas comes into one's own gradually.The expired gas detection is compared with traditional method, and it has easy and noninvasive characteristics, and therefore a large amount of researchs about the expired gas biomarker are arranged.There is research to point out that the rising of nitric oxide level in the expired gas takes place relevant with asthma, the level of antioxidant is relevant with the COPD progress, cytokine is relevant with the cystic fibrosis generation with chemotactic factor, and hydrogen peroxide, decane and isoprene are relevant with the generation of nonsmall-cell lung cancer.Even have some expired gas biomarkers to be applied to clinical (for example detecting nitric oxide in the asthmatic patient expired gas), other then be mainly used in clinical research (for example VOC).The existing report of research and development by organic compound (VOC) diagnosing and relevant device in the detection expired gas.It is little that the equipment that detects VOC has volume usually, do not have traumaticly, grasps easily and use and lower-price characteristic, and this is significant to the efficient that improves diagnosing and other respiratory system diseases.But above-mentioned research only detects existence and the concentration of chemical substance in the breath, and they can not provide diseased region or the Airway Remodeling level that produces these chemical substances, and these two be the key of pulmonary carcinoma and the treatment of some pulmonary disease.
At present, can only be by the position of the clear and definite pathological changes of iconography technology such as CT or PET.But this technical costs is higher and have a Radio Active Hazard.More important is that it can not carry out the treatment of targeted drug.Therefore, select a kind of method safer, that price is more cheap extremely urgent.
Computational fluid dynamics (Computational Fluid Dynamics, be called for short CFD) is to calculate and the image demonstration by computer numerical, the analysis that the system that includes relevant physical phenomenas such as fluid flow and conduction of heat is done.At present the international and domestic scholar of having sets up model research by the computational fluid dynamics method, relates generally to the cardiovascular aspect, and the research of relevant respiratory system seldom and detects the research discovery as yet of pulmonary disease about the aerosol expired gas.
Summary of the invention
In order to solve the above-mentioned technical problem that exists in the background technology, the invention provides the modeling method based on aerosol expired gas detection pulmonary disease that a kind of feasibility is high and clinical diagnosis is had directive significance.
Technical solution of the present invention is: the invention provides a kind of modeling method based on aerosol expired gas detection pulmonary disease, its special character is: said method comprising the steps of:
1) sets up human lung's structural model;
2) human lung's structural model that step 1) is set up sucks and has fluorescently-labeled aerosol particle;
Having 3) step 2) collected with membrane filter after fluorescently-labeled aerosol particle passes through human lung's mold cycle;
4) the collected fluorescently-labeled aerosol particle that has that obtains of membrane filter is carried out qualitative analysis and quantitative analysis;
5) judge diseased region and the lesion degree of pulmonary disease according to the result of the resulting qualitative analysis of step 4) and/or quantitative analysis.
Above-mentioned steps 1) specific implementation is:
1.1) utilize GAMBIT, AUTOCAD or PROE software to set up human lung's structural model;
1.2) measure the value of biofluid dynbamics material behavior and this value is invested step 1.1) in human lung's structural model of setting up;
1.3) human lung's structural model carried out the emulation of experimental condition; Described emulation comprises the hydrodynamics experiment condition of geometrical constraint, constantly acting load, shock loading, temperature characterisitic, blood flow, blood pressure, thrombosis retardance and 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 of suffering from the trachea carina tumor, the lung model of suffering from the lung model of tumor of bronchus and suffering from the asthma bronchospasm.
Above-mentioned steps 1) human lung's structural model of setting up is two-dimension human body pulmonary structural model or 3 D human body pulmonary structural model.
Above-mentioned steps 2) aerosol is the fluorescein-labeled aerosol particle of monodispersed enuatrol that is produced by vibrations hole monodisperse aerosol generator or the polystyrene fluorescence solution aerosol particle that is produced by medical vaporizer in; The particle diameter of described aerosol particle is 2-10 μ m.
Above-mentioned steps 2) making human lung's structural model suck the suction flow velocity that has fluorescently-labeled aerosol particle in is 20～30L/min.
Above-mentioned steps 4) qualitative analysis in is that the collected fluorescently-labeled aerosol particle that has that obtains of step 3) is carried out colorimetric, analyzes by color and brightness that aerosol particle concentration produces.
Above-mentioned steps 4) quantitative analysis in is with optical microscope the collected fluorescently-labeled aerosol particle that has that obtains of step 3) to be carried out grain count.
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 the patient sucks harmless fluorescent labeling aerosol particle, can manifest a kind of chaos, unordered pattern of seeming.Yet 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.The bronchial aerosol fingerprint of each bar is finally with a kind of special pattern of the common composition of breath.Therefore, any bronchial pathological changes all can change the formation of aerosol fingerprint, thereby provides foundation for diagnosing the illness.Certainly, the result that this just draws by the simulation human airway need further verify its feasibility and effectiveness by clinical trial.This research is intended to by contrast clinical trial and CFD analog result, further this inspection of checking is at feasibility and the effectiveness of clinical implementation, develop a kind of new pulmonary disease detection method, make up the data base of relevant human airway simultaneously, lay the foundation for further carrying out correlational study.
The present invention has characteristics such as noinvasive, easy to operate, "dead", low price, is applicable to the patient that can not tolerate traumatic inspection and radioexmination, and part does not have the medical institutions of checkout facilities such as CT/PET.If through clinical its effectiveness of further confirmation, can be used as the conventional examination of patients with lung cancer, this brings considerable economic and social benefit will for medical institutions and society.The development of medical science is closely related with development in Hi-Tech all the time." digital virtual human body " utilizes computer image technology and combines with clinical anatomy, realized structure and the digitized of function, visual of human body from the microcosmic to the macroscopic view, tissue has intactly been described so that the form and function of organ, finally reach the whole accurately simulation of human body information, for medical science, life science and application provide technical support.The digital virtual human body is the front subject that information technology and medical science cross-synthesis grow up, and the 21 century development in science and technology is had far reaching significance.
The present invention utilizes the air flue of computational fluid dynamics simulation human body, finds a certain size aerosol particle at the intrabronchial flow trace of different-diameter, determines position and the degree of pathological changes by this, and it has noinvasive, advantage such as convenient, real-time.If popularized clinically, bring major transformation will for the diagnosis and treatment of pulmonary disease.Of the present inventionly be embodied as clear and definite pulmonary disease a kind of easy, quick, noinvasive and cheap new diagnostic method are provided, be specially adapted to some and can not tolerate the patient that wound inspection maybe can not be accepted radioexmination.It can provide the targeted drug treatment simultaneously, reduces the untoward reaction that the systemic drug treatment brings, and increases the drug level of local patholoic change treatment, has improved the cure rate of disease, and is all significant to patient and society.
Description of drawings
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 of suffering from the trachea carina tumor that the present invention sets up;
Fig. 1 c is the lung model structural representation of suffering from tumor of bronchus that the present invention sets up;
Fig. 1 d is the lung model structural representation of suffering from the asthma bronchospasm that the present invention sets up;
To be the lung model set up among Fig. 1 a form the pattern sketch map at the aerosol of variable grain to Fig. 2 a;
To be the lung model set up among Fig. 1 b form the pattern sketch map at the aerosol of variable grain to Fig. 2 b;
To be the lung model set up among Fig. 1 c form the pattern sketch map at the aerosol of variable grain to Fig. 2 c;
To be the lung model set up among Fig. 1 d form the pattern sketch map at the aerosol of variable grain to Fig. 2 d;
Fig. 3 breathe out when being the asthma state aerocolloidal pattern and the comparison diagram of expired gas colloidal sol pattern just often;
Fig. 4 is the initial position view that discharges of granule of the pulmonary lesion deposition of the lung model set up among Fig. 1 a to Fig. 1 d.
The specific embodiment
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 the patient sucks harmless fluorescent labeling aerosol particle, can manifest a kind of chaos, unordered pattern of seeming.Yet 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 the bar bronchus in the air flue all can produce a kind of its distinctive pattern, can be referred to as the aerosol fingerprint (aerosol fingerprint, AFP).The bronchial aerosol fingerprint of each bar is finally with a kind of special pattern of the common composition of breath.Therefore, any bronchial pathological changes all can change the formation of aerosol fingerprint, thereby provides foundation for diagnosing the illness.Certainly, the result that this just draws by the simulation human airway need further verify its feasibility and effectiveness by clinical trial.This research is intended to by contrast clinical trial and CFD analog result, further this inspection of checking is at feasibility and the effectiveness of clinical implementation, develop a kind of new pulmonary disease detection method, make up the data base of relevant human airway simultaneously, lay the foundation for further carrying out correlational study.
Breath can be pointed out the clue of a lot of diseases.Because the variation of lung tumors cellular metabolism can cause the change of certain chemical substance, therefore can produce special breath, this just can be used for detecting disease.At medical domain, fluid model is the biofluid dynbamics characteristics of researching human body better.Human body has very complicated structure, and utilize GAMBIT, AUTOCAD, the modeling function of softwares such as PROE, can set up two dimension, the 3 D human body structural model, and a biofluid dynbamics material behavior of measuring by hydrodynamic methods invests this model, in computer, set up virtual " experimental specimen ", then to the model condition emulation (geometrical constraint that experimentizes, constantly acting load, shock loading, temperature characterisitic etc.), simulate blood flows, blood pressure, the thrombosis retardance, hydrodynamics experiment conditions such as respiratory system, can obtain this virtual objects and the similar hydrodynamics index of experimental specimen, for example blood flow rate and the blood pressure of any part of object (comprising aneurysm etc.) by finding the solution, the internal energy variations in temperature, situations of change such as limit destruction.CFD research has the incomparable advantage of experimental technique: it can produce numerous various specimen as required, same specimen can load many times or make up and can not be damaged in virtual calculating, and specimen also can revise to simulate any pathological state.
Have at present in a large number about the researchs of expired gas biomarker, detect in the asthmatic patient expired gas nitric oxide production level be applied to clinical, significant aspect diagnosis and Differential Diagnosis asthma.VOC has been applied to clinical research in detection of lung cancer patient's expired gas.But since existing expired gas detect can not clear and definite diseased region and degree, its clinical practice is subjected to certain limitation.Can predict, bring huge social benefit and economic benefit if aerosol expired gas detection is applied to clinical patient and the society of will giving.
For the feasibility of this method is described, the present invention utilizes the computational fluid dynamics method to simulate 6 grades of bronchial desirable lung model from oral cavity to the.One has 4 models, is respectively normal air flue (ModelA, Fig. 1 a), trachea carina tumor (Model B), tumor of bronchus (Model C), asthma bronchospasm (Model D) (Fig. 1 b-Fig. 1 d).The details of 4 kinds of models see Table 1.Different air flue geometry forms can produce different aerosol exhalation fingerprints, and key is the internal relation of understanding between the two.The lung model of having represented various various disease characteristics in Fig. 1: 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 characteristics of the different air flue models of table 1.
In order to simulate the aerosol fingerprint detection, aerocolloidal suction and exhalation are all carried out under steady statue.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 (referring to 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 the bronchial enlargement tumor, and Fig. 2 c is that left bronchus tumor and Fig. 2 d are asthma.The granule that 3 kinds of sizes are arranged: 1 μ m, 5 μ m and 10 μ m.Expired gas colloidal sol pattern is the fingerprint of air passage structure, therefore can be used to accurately locate the position of abnormality.Expired gas colloidal sol pattern is difference (being similar to finger) with the change in size that sucks aerosol particle, and this also can be used to infer position and the period of lung tumors.
More significantly, each model all has its specific expired gas colloidal sol pattern, and this can help to judge position and the scope of pathological changes.For any model, although the aerosol particle of different size (0.4 –, 5 μ m) pattern changes, but similarity is arranged.For example, the expired gas colloidal sol pattern of Model D have in its upper left corner one crescent, 3 models of this and other are obviously different, but all big or small aerosol particles of this model have this similar pattern.Because Model D has simulated the bronchioles spasm, therefore the appearance of this figure hint bronchioles spasm exists.This observation has confirmed that expired gas colloidal sol pattern is a kind of and the hypothesis of the aerosol fingerprint of pulmonary's structurally associated.
This hypothesis can further be verified by only detecting aerosol particle from diseased region.For example, two bronchioles spasm (referring to Fig. 3) are arranged among the Medel D.The clear-cut of red granules, and can be used as the indicator of asthma state.At last, can also be used to assessing as the location of disease the concrete position of air flue spasm.Fig. 3 is asthma state and the comparison of expired gas colloidal sol pattern just often.Red granules in the asthma state expired gas colloidal sol pattern is from the bronchioles of two spasm.The granule of these change color can be used to the level to pulmonary disease location and assessment air flue spasm.
After having determined the position and the order of severity of pathological changes, can drug dose accurately be sent to the affected part bronchus according to the degree of pathological changes.About targeted drug treatment, most critical be the position that clear and definite medicine arrives.For this problem is described, at first discharge aerosol particle in buccal, follow the trail of granule in pulmonary deposition according to its regioselectivity that discharges in buccal.Fig. 4 has shown the off-position of pulmonary lesion position deposited particles.In theory, if discharge the pharmaceutical aerosol granule at these positions, all granules all can return the position of its pathological changes and be deposited on the there, and this has just realized the targeted drug treatment.Be deposited on the aerosol particle of privileged sites all from clear and definite bronchus.Simultaneously, because the left and right sides 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.For example, main bronchioles diameter is 1mm only, and terminal bronchiole is 0.5mm or thinner only, and the respiratory bronchioles diameter is 0.2mm only.And ill lung tissue structure is more complicated.The aerosol expired gas detects whether can obtain similar result of study at human body, with and the feasibility of manipulation check need clinical trial further to verify.
Plan is chosen 10 patients with lung cancer clinically, 10 asthmatic patients, and 10 normal persons compare checking.The inclusion criteria of patients with lung cancer: 1) meet diagnostic criteria in the Ministry of Public Health pulmonary carcinoma practice guidelines (2011); 2) the first discovery, previously the foundation-free disease shifts in the apneumia, does not perform an operation and chemicotherapy; Asthmatic patient inclusion criteria: 1) meet diagnostic criteria in the prevention and control of bronchial asthma guide (2008); 2) there are not the pulmonary heart disease of merging, respiratory failure.Normal person's inclusion criteria: 1) previously do not have any underlying diseases; 2) can tolerate coherence check.Through the examination of Ethics Committee of Affiliated Hospital of Xi'an Medical University and approval, all devices and reagent are harmless.All patients (except the normal person) all need be in hospital, and sign Informed Consent Form, and record the general datas such as Diagnostic Time, treatment situation and physical examination of its disease, 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.The normal person does not require and carries out CT scan.All personnel carries out aerosol atomizing suction detection afterwards, and concrete grammar is as follows:
1) sucks aerosol particle: allow the tranquil suction of experimenter by vibrations hole monodisperse aerosol generator (VOAG, Model3050, TSI, Inc St.Paul, MN) aerosol particle of Chan Shenging.It will produce the fluorescein-labeled aerosol of monodispersed enuatrol (having confirmed harmless), and diameter 2-10 μ m also needs a pressurizing tank that lasting, stable liquid solution is provided simultaneously.This improved system can continue a few hours generation aerosol particle.In addition, (TSI Inc), is used for monitoring and adjusting aerosol particle size also to need a grain spectrometer.Aerosol particle diameter＜2 μ m if desired, with a medical vaporizer (Hospitak, Lindenhurst, NY) produce polystyrene fluorescence solution aerosol (Duke Scientific, Palo Alto, CA).Flow velocity is arranged on 20～30L/min, the breathing flow velocity when this is adult's seat and slight motion substantially.
2) collect breath: advise the tranquil expiration of experimenter behind the tranquil suction aerosol.Collect breath in buccal with membrane filter.When gas was breathed out, little microgranule was by the hole of membrane filter, and big microgranule is then stayed the surface of membrane filter.In addition, also need the adnexa of filter sampling: the ACCU-CAP tape inserts adapter, tank prover, and the boxlike blank is held filter box, filter support, transportation adnexa filter, helmet adapter, contraction bands, pipe and spider.
3) analyze the aerosol breath: with two kinds of methods analyst results, qualitative and quantitative.
Qualitative: as can to produce different color and brightness according to the concentration of aerosol particle with fluorescein imaging colorimetric aerosol.
Quantitatively: (Tokyo Japan) carries out grain count for Optiphot-66, Nikon with optical microscope.
Claims (8)
1. one kind is detected the modeling method of pulmonary disease based on the aerosol expired gas, it is characterized in that: said method comprising the steps of:
1) sets up human lung's structural model;
2) human lung's structural model that step 1) is set up sucks and has fluorescently-labeled aerosol particle;
Having 3) step 2) collected with membrane filter after fluorescently-labeled aerosol particle passes through human lung's mold cycle;
4) the collected fluorescently-labeled aerosol particle that has that obtains of membrane filter is carried out qualitative analysis and quantitative analysis;
5) judge diseased region and the lesion degree of pulmonary disease according to the result of the resulting qualitative analysis of step 4) and/or quantitative analysis.
2. according to claim 1ly detect the modeling method of pulmonary disease based on the aerosol expired gas, it is characterized in that: the specific implementation of described step 1) is:
1.1) utilize GAMBIT, AUTOCAD or PROE software to set up human lung's structural model;
1.2) measure the value of biofluid dynbamics material behavior and this value is invested step 1.1) in human lung's structural model of setting up;
1.3) human lung's structural model carried out the emulation of experimental condition; Described emulation comprises the hydrodynamics experiment condition of geometrical constraint, constantly acting load, shock loading, temperature characterisitic, blood flow, blood pressure, thrombosis retardance and respiratory system.
3. according to claim 2ly detect the modeling method of pulmonary disease based on the aerosol expired gas, it is characterized in that: human lung's structural model that described step 1) is set up comprises the lung model with normal air flue, the lung model of suffering from the trachea carina tumor, the lung model of suffering from the lung model of tumor of bronchus and suffering from the asthma bronchospasm.
4. according to claim 3ly detect the modeling method of pulmonary disease based on the aerosol expired gas, it is characterized in that: human lung's structural model that described step 1) is set up is two-dimension human body pulmonary structural model or 3 D human body pulmonary structural model.
5. detect the modeling method of pulmonary disease according to the arbitrary claim of claim 1 to 4 is described based on the aerosol expired gas, it is characterized in that: aerosol is the fluorescein-labeled aerosol particle of monodispersed enuatrol that is produced by vibrations hole monodisperse aerosol generator or the polystyrene fluorescence solution aerosol particle that is produced by medical vaporizer described step 2); The particle diameter of described aerosol particle is 2-10 μ m.
6. according to claim 5ly detect the modeling method of pulmonary disease based on the aerosol expired gas, it is characterized in that: making human lung's structural model suck the suction flow velocity that has fluorescently-labeled aerosol particle described step 2) is 20～30L/min.
7. the modeling method that detects pulmonary disease based on the aerosol expired gas according to claim 6, it is characterized in that: the qualitative analysis in the described step 4) is that the collected fluorescently-labeled aerosol particle that has that obtains of step 3) is carried out colorimetric, analyzes by color and brightness that aerosol particle concentration produces.
8. according to claim 7ly detect the modeling method of pulmonary disease based on the aerosol expired gas, it is characterized in that: the quantitative analysis in the described step 4) is with optical microscope the collected fluorescently-labeled aerosol particle that has that obtains of step 3) to be carried out grain count.
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