颗粒物在人体呼吸系统中传输与沉积的数值模拟研究
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摘要
颗粒污染物随着呼吸过程进入人体并沉积在呼吸道内部,导致沉积表面细胞的氧化应激反应,危害人体健康。近年来,流行病学研究表明,大气中可吸入颗粒物浓度的上升导致呼吸系统疾病、心血管疾病发病率及死亡率的增加。因此,研究在呼吸道内颗粒物的沉积对于评估颗粒污染物的健康风险至关重要。另一方面,颗粒药物通过呼吸系统直接作用与病患处治疗疾病具有靶向性高、起效迅速等优点,近年来被认为是一种很有前途的治疗方式。研究颗粒药物在呼吸道内的沉积对于改善吸入疗法的疗效具有重要的参考价值。
在呼吸生理学及人体肺部结构的研究基础上,引入人体的基本呼吸参数,建立肺部第三级到第六级健康及阻塞支气管的物理模型,通过数值模拟来研究气体流动及颗粒物沉积规律。选择欧拉-拉格朗日模型来研究空气流动和颗粒物的运行轨迹,其控制方程分别为N-S方程和牛顿第二定律方程,通过计算得出模型中空气流场的分布特性和颗粒物沉积结果。颗粒物的沉积量和沉积部位是评估颗粒物对人体健康影响的重要参数,呼吸速率和颗粒物的属性是影响其沉积量和沉积部位的主要因素。本文主要研究了以下内容：1.通过改变模型入口的气体雷诺数,研究得出人体处于不同呼吸强度下颗粒物的沉积情况。2.研究颗粒物粒径和密度对沉积的影响,研究得出不同属性的颗粒物质在人体的沉积特性。3.通过调节重力与计算模型的相对方向,来模拟实际情况中重力对颗粒物沉积及药物靶向性的调节作用。
通过与他人实验及模拟结果的对比,验证了本文的模拟结果的可靠性。研究表明,粒径在2.5-10μm的颗粒物总沉积量随入口雷诺数增加而增加,入口速度分布对流场和颗粒物沉积均有明显影响。对于粒径在0.1～10μm的颗粒物,粒径越小在模型中总沉积量越低；低雷诺数条件下重力在对颗粒物沉积的影响明显。通过调节呼吸速率和药物的物理属性可以改善治疗的靶向效果,10μm的颗粒物在Re=2000时靶向效果达到最优,颗粒物的密度和重力方向对沉积的靶向性均有不同程度的影响。
Particle deposition in respiratory tract could increase human oxidative stress and then may cause airway inflammation et al, Recently, epidemiology researches find out increasing concentration of inhalable particulate matter led to the rise of morbidity and mortality in respiratory diseases, cardiovascular diseases. Therefore, the research of particle deposition in the human lung is essential to the health risk assessment of particulate pollutants. On the other side, inhaling medicines therapy, which means delivering drugs to the body through the lungs, is recognized as a versatile, highly promising and until recently little exploited route for drug delivery worldwide, the study of inhaling drug deposition in the respiratory tract provides an important reference value to improve the efficacy of inhalation therapy.
Based on respiratory physiology and human lung structure, the respiratory and airway parameters were applied to the research, physical model of health and obstruction bronchial from the 3rd generation to 6th generation were established. Euler-Lagrange method was selected to simulate the air flow and particulate matter trajectory, N-S equation and Newton's second law were taken as the control equations; Through numerical simulation, the airflow and particle deposition were analyzed, the targeting drug delivery in the obstruction airway were optimized, the airflow field distribution and the particle deposition results were taken to show the characteristic of airflow and particle movement in human airways system. Particles deposition rate and region are the critical parameters for the assessment of particles effects on human health, the airflow field and particle physical properties are the main factors that affect the deposition conditions, first, by changing the airflow Reynolds number at model entrance, deposition of particulate matter in the human airways at different respiration rate were obtained; second, particle diameter and density were the key factors to the deposition, results in characteristics of particulate matter with different properties of deposition in the human airways were studied; third, adjusting the relative orientation of gravity and the physical model, the gravity on the particles deposition and regulation of drug targeting is achieved.
The numerical methods were validated by comparing the simulation results with experimental results. Research shows that the total deposition concentration of particles lager than 2.5μm in diameter increases with entrance Reynolds number, the inlet velocity distribution significantly affected the airflow field and particle deposition. For the particles diameter between 0.1-10μm, the smaller the particle size, the total deposition is lower in the model; the gravity effect on particle deposition is more significant under low Reynolds number conditions. Particulate pollutants in the obstructed bronchial may lead to further deterioration of obstructive symptoms, 10μm particles in the inlet air Reynolds number for the 2000 target coefficient is the maximal value, particle density and the direction of gravity on the deposition of the targeting effects. Through this research, a theoretical basis for further understanding of particles and the relationship between human health and the drug delivery mechanism was provided.
在呼吸生理学及人体肺部结构的研究基础上,引入人体的基本呼吸参数,建立肺部第三级到第六级健康及阻塞支气管的物理模型,通过数值模拟来研究气体流动及颗粒物沉积规律。选择欧拉-拉格朗日模型来研究空气流动和颗粒物的运行轨迹,其控制方程分别为N-S方程和牛顿第二定律方程,通过计算得出模型中空气流场的分布特性和颗粒物沉积结果。颗粒物的沉积量和沉积部位是评估颗粒物对人体健康影响的重要参数,呼吸速率和颗粒物的属性是影响其沉积量和沉积部位的主要因素。本文主要研究了以下内容：1.通过改变模型入口的气体雷诺数,研究得出人体处于不同呼吸强度下颗粒物的沉积情况。2.研究颗粒物粒径和密度对沉积的影响,研究得出不同属性的颗粒物质在人体的沉积特性。3.通过调节重力与计算模型的相对方向,来模拟实际情况中重力对颗粒物沉积及药物靶向性的调节作用。
通过与他人实验及模拟结果的对比,验证了本文的模拟结果的可靠性。研究表明,粒径在2.5-10μm的颗粒物总沉积量随入口雷诺数增加而增加,入口速度分布对流场和颗粒物沉积均有明显影响。对于粒径在0.1～10μm的颗粒物,粒径越小在模型中总沉积量越低；低雷诺数条件下重力在对颗粒物沉积的影响明显。通过调节呼吸速率和药物的物理属性可以改善治疗的靶向效果,10μm的颗粒物在Re=2000时靶向效果达到最优,颗粒物的密度和重力方向对沉积的靶向性均有不同程度的影响。
Particle deposition in respiratory tract could increase human oxidative stress and then may cause airway inflammation et al, Recently, epidemiology researches find out increasing concentration of inhalable particulate matter led to the rise of morbidity and mortality in respiratory diseases, cardiovascular diseases. Therefore, the research of particle deposition in the human lung is essential to the health risk assessment of particulate pollutants. On the other side, inhaling medicines therapy, which means delivering drugs to the body through the lungs, is recognized as a versatile, highly promising and until recently little exploited route for drug delivery worldwide, the study of inhaling drug deposition in the respiratory tract provides an important reference value to improve the efficacy of inhalation therapy.
Based on respiratory physiology and human lung structure, the respiratory and airway parameters were applied to the research, physical model of health and obstruction bronchial from the 3rd generation to 6th generation were established. Euler-Lagrange method was selected to simulate the air flow and particulate matter trajectory, N-S equation and Newton's second law were taken as the control equations; Through numerical simulation, the airflow and particle deposition were analyzed, the targeting drug delivery in the obstruction airway were optimized, the airflow field distribution and the particle deposition results were taken to show the characteristic of airflow and particle movement in human airways system. Particles deposition rate and region are the critical parameters for the assessment of particles effects on human health, the airflow field and particle physical properties are the main factors that affect the deposition conditions, first, by changing the airflow Reynolds number at model entrance, deposition of particulate matter in the human airways at different respiration rate were obtained; second, particle diameter and density were the key factors to the deposition, results in characteristics of particulate matter with different properties of deposition in the human airways were studied; third, adjusting the relative orientation of gravity and the physical model, the gravity on the particles deposition and regulation of drug targeting is achieved.
The numerical methods were validated by comparing the simulation results with experimental results. Research shows that the total deposition concentration of particles lager than 2.5μm in diameter increases with entrance Reynolds number, the inlet velocity distribution significantly affected the airflow field and particle deposition. For the particles diameter between 0.1-10μm, the smaller the particle size, the total deposition is lower in the model; the gravity effect on particle deposition is more significant under low Reynolds number conditions. Particulate pollutants in the obstructed bronchial may lead to further deterioration of obstructive symptoms, 10μm particles in the inlet air Reynolds number for the 2000 target coefficient is the maximal value, particle density and the direction of gravity on the deposition of the targeting effects. Through this research, a theoretical basis for further understanding of particles and the relationship between human health and the drug delivery mechanism was provided.
引文
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[2]Brunekreef B, Holgate ST. Air pollution and health [J]. Lancet,2002,360: 1233-1242.
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[6]Shirzad A, Roa WH, et al. Targeted delivery of nanoparticles for the treatment of lung diseases [J]. Advanced Drug Delivery Reviews,2008,60:863-875.
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[11]Oberdorster G, Utell MJ. Ultrafine particles in the urban air:to the respiratory tract-and beyond? [J]. Environmental Health Perspectives,2002,110:440-441.
[12]Brunekreef B. Air pollution and life expectancy:is there a relation? [J]. Occupational and Environmental Medicine,1997,54:781-784.
[13]Rogers JF, AL Dunlop. Air pollution and very low birth weight infants:a target population [J]. Pediatrics,2006,118:156-164.
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[19]时宗波,邵龙义.城市大气可吸入颗粒物对质粒DNA的氧化损伤[J].科学通报,2004,49(7)：673-678.
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[23]刘韬.吸入疗法中呼吸道内流体运动状况的数值模拟[D].上海：东华大学,2007.
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[25]曾敏捷.可吸入颗粒物在人体上呼吸道中运动沉积的数值模拟[D].杭州：浙江大学,2005.
[26]尹景娟.颗粒物在人体上呼吸道内运动沉降规律的研究[D].北京：北京交通大学,2006.
[27]Katrin A, Brucker C. Dynamic flow in a realistic model of the upper human lung airways [J]. Experiments in Fluids,2007,43:411-423.
[28]Morawska L, Hofmann W, Loveday J H. Experimental study of the deposition of combustion aerosols in the human respiratory tract [J]. Aerosol Science,2005,36: 939-957.
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[31]Horsfield K, Dart G, Olson DE, et al. Models of the human bronchial tree [J]. Journal of Applied Physiology,1971,31:207-217.
[32]Balashazy I, Hofmann W. Deposition of aerosols in asymmetric airway bifurcations [J]. Journal of Aerosol Science,1995,30:185-203.
[33]Kim CS, Fisher DM. Deposition characteristics of aerosol particles in sequentially bifurcating airway models [J]. Aerosol Science and Technology, 1999,31:198-220.
[34]Sarangapani R, Wexler AS. Modeling aerosol bolus dispersion in human airways [J]. Journal of Aerosol Science,1999,30(10):1345-1362.
[35]Zhang Z, Kleinstreuer C. Effect of particle Inlet distributions on deposition in a triple bifurcation lung airway model [J]. Journal of Aerosol Medicine,2001, 14(1):13-29.
[36]Hogberg S. Particle deposition in conducting airways using CFD [D]. Lulea: Lulea University of Technology,2006.
[37]Longest W, Xi JX. Computational investigation of particle inertia effects on submicron aerosol deposition in the respiratory tract [J]. Journal of Aerosol Science,2007,38:111-130.
[38]Li Z, Kleinstreuer C, et al. Simulation of airflow fields and microparticle deposition in realistic human lung airway models [J]. European Journal of Mechanics B/Fluids,2007,26:632-649.
[39]Hofmann W, et al. Simulation of three-dimensional particle deposition patterns in human lungs and comparison with experimental SPECT data [J]. Aerosol Science and Technology,2005,39:771-781.
[40]Longest W, Vinchurkar S. Effects of mesh style and grid convergence on particle deposition in bifurcating airway models with comparisons to experimental data [J].Medical Engineering & Physics,2007,29:350-366.
[41]Kleinstreuer C, Zhang Z, et al. Combined inertial and gravitational deposition of microparticles in small model airways of a human respiratory system [J]. Journal of Aerosol Science,2007,38:1047-1061.
[42]Ounis H, Ahmadi G. Analysis of dispersion of small spherical particles in a random velocity field [J]. Fluids England.1990,112:114-120.
[43]Kleinstreuer C. Biofluid dynamics—Principles and selected applications [M]. Boca Raton. FL:CRC Press,2006.
[44]Farkas A, Balashazy I. Quantification of particle deposition in asymmetrical tracheobronchial model geometry [J]. Computers in Biology and Medicine,2008, 38:508-518.
[45]Zhao Y and Lieber BB. Steady inspiratory flow in a model symmetric bifurcation [J]. ASME Journal of Biomechanical Engineering,1994,116:488-496.
[46]Liu Y, So, RMC, Zhang, CH. Modeling the bifurcating flow in a human lung airway [J]. Journal of Biomechanics,2002,35:477-485.
[47]Lippmann M. Regional deposition of particles in the human respiratory tract. In D. H. K. Lee et al. (Eds.), Handbook of physiology—reaction to environmental agents [M] Bethesda, MD:American Physiology Society,1977,213-232.
[48]Emmett PC, Aitken RJ,& Hannan WJ. Measurements of the total and regional deposition of inhaled particles in the human respiratory-tract [J]. Journal of Aerosol Science,1982,13(6):549-560.
[49]Foord N, Black A,& Walsh M. Regional deposition of 2.5-7.5 μm diameter inhaled particles in healthy male non-smokers [J]. Journal of Aerosol Science, 1978,9:343-357.
[50]Chan, TL,& Lippmann M. Experimental measurements and empirical modeling of the regional deposition of inhaled particles in humans [J]. American Industrial Hygiene Association Journal,1980,41(6):399-408.
[51]Comer JK, Kleinstreuer C, Zhang Z. Flow structures and particle deposition patterns in double-bifurcation airway models Part 1. Airflow fields [J]. Journal of Fluid Mechanics,2001,435:25-54.
[52]Slutsky A, Berdine G, Drasen J. Steady flow in a model of human central airways [J]. Journal of Applied Physiology,1980,49:417-423.
[53]Pedley TJ, Kamm R. Dynamics of gas flow and pressure-flow relationships. In: Crystal, R., West, J. (Eds.), the Lung:Scientific Foundations [M]. Raven Press Ltd., New York,1991,995-1010.
[54]Davis ME, Chen Z, et al. Nanoparticle therapeutics:an emerging treatment modality for cancer [J]. Nature Reviews Drug Discovery,2008,7:771-782.
[55]Kreuter J. Nanoparticulate systems for brain delivery of drugs [J]. Advanced Drug Delivery Reviews,2001,47:65-81.
[56]Broday D. Deposition of ultrafine particles at carinal ridges of the upper bronchial airways [J]. Aerosol Science and Technology,2004,38(10):991-1000.
[57]Isaacs KK, Martonen TB. Particle deposition in children's lungs:theory and experiment [J]. Journal of Aerosol Medicine,2005,18(3):337-353.
[58]Dames P, Gleich B, Flemmert A, et al. Targeted delivery of magnetic aerosol droplets to the lung [J]. Nature Nanotechnology,2007,2:495-499.
[2]Brunekreef B, Holgate ST. Air pollution and health [J]. Lancet,2002,360: 1233-1242.
[3]Dominici F, Peng RD, et al. Fine particulate air pollution and hospital admission for cardiovascular and respiratory diseases [J]. Journal of the American Medical Association,2006,295:1127-1134.
[4]Gonzalez-Flecha B. Oxidant mechanisms in response to ambient air particles [J]. Molecular Aspects of Medicine,2004,25:169-182.
[5]Coates AL. Guiding aerosol deposition in the lung [J]. New England Journal of Medicine,2008,358(3):304-305.
[6]Shirzad A, Roa WH, et al. Targeted delivery of nanoparticles for the treatment of lung diseases [J]. Advanced Drug Delivery Reviews,2008,60:863-875.
[7]Dames P, Gleich B, et al. Targeted delivery of magnetic aerosol droplets to the lungs[J]. Nature Nanotechnology,2007,2:495-499.
[8]Rosen H, Abribat T. Timeline:The rise and rise of drug delivery [J]. Nature Reviews Drug Discovery,2005,4(5):1-5.
[9]Mage D T.A particle is not a particle is not a PARTICLE [J]. Journal of Exposure Analysis and Environmental Epidemiology,2002,12:93-95.
[10]Nemmar A, Hoet PHM, et al. Passage of inhaled particles into the blood circulation in humans [J]. Circulation,2002,105:411-414.
[11]Oberdorster G, Utell MJ. Ultrafine particles in the urban air:to the respiratory tract-and beyond? [J]. Environmental Health Perspectives,2002,110:440-441.
[12]Brunekreef B. Air pollution and life expectancy:is there a relation? [J]. Occupational and Environmental Medicine,1997,54:781-784.
[13]Rogers JF, AL Dunlop. Air pollution and very low birth weight infants:a target population [J]. Pediatrics,2006,118:156-164.
[14]Anderson HR, Atkinson RW, Peacock JL, et al. Meta-analysis of time series studies and panel studies of particulate matter (PM) and ozone (O3) [M]. Denmark:WHO Regional Office for Europe,2004:1-73.
[15]Pope CA, Burnett RT, Thun MJ, et al. Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution [J]. Journal of the American Medical Association,2002,287(9):1132-1141.
[16]Samet JM, Dominici F, Curriero FC, et al. Fine particulate air pollution and mortality in 20 U.S. cities,1987-1994 [J]. New England Journal of Medicine, 2000,343(24):1742-1749.
[17]Pope CA, Muhlestein JB, May HT, et al. Ischemic heart disease events triggered by short-term exposure to fine particulate air pollution [J]. Circulation,2006, 114(13):2443-2448.
[18]Peter M, Janne K, Folkmann L. Air pollution, oxidative damage to DNA, and carcinogenesis [J]. Cancer Letters,2008,266:84-97.
[19]时宗波,邵龙义.城市大气可吸入颗粒物对质粒DNA的氧化损伤[J].科学通报,2004,49(7)：673-678.
[20]金泰廙.现代毒理学[M].上海：复旦大学出版社,2004
[21]Barnes PJ. Chronic Obstructive Pulmonary Disease [J]. New England Journal of Medicine,2000,343(4):269-280.
[22]Patton JS, Byron PR. Inhaling medicines:delivering drugs to the body through the lungs [J]. Nature Reviews/Drug Discovery,2007,6:67-74.
[23]刘韬.吸入疗法中呼吸道内流体运动状况的数值模拟[D].上海：东华大学,2007.
[24]Lippmann M, Yeates DB, and Albert RE. Deposition, retention, and clearance of inhaled particles [J]. Occupational Environment Medicine.1980,37:337-362.
[25]曾敏捷.可吸入颗粒物在人体上呼吸道中运动沉积的数值模拟[D].杭州：浙江大学,2005.
[26]尹景娟.颗粒物在人体上呼吸道内运动沉降规律的研究[D].北京：北京交通大学,2006.
[27]Katrin A, Brucker C. Dynamic flow in a realistic model of the upper human lung airways [J]. Experiments in Fluids,2007,43:411-423.
[28]Morawska L, Hofmann W, Loveday J H. Experimental study of the deposition of combustion aerosols in the human respiratory tract [J]. Aerosol Science,2005,36: 939-957.
[29]Weibel ER. Morphometry of the Human Lung [M]. Academic Press, New York, Springer, Berlin,1963.
[30]Raabe OG, Yeh HC, Schum GM, et al. Tracheobronchial Geometry:Human, Dog, Rat, HamsterLF-53 [M]. Lovelace Foundation Report, Albuquerque, New Mexico,1976.
[31]Horsfield K, Dart G, Olson DE, et al. Models of the human bronchial tree [J]. Journal of Applied Physiology,1971,31:207-217.
[32]Balashazy I, Hofmann W. Deposition of aerosols in asymmetric airway bifurcations [J]. Journal of Aerosol Science,1995,30:185-203.
[33]Kim CS, Fisher DM. Deposition characteristics of aerosol particles in sequentially bifurcating airway models [J]. Aerosol Science and Technology, 1999,31:198-220.
[34]Sarangapani R, Wexler AS. Modeling aerosol bolus dispersion in human airways [J]. Journal of Aerosol Science,1999,30(10):1345-1362.
[35]Zhang Z, Kleinstreuer C. Effect of particle Inlet distributions on deposition in a triple bifurcation lung airway model [J]. Journal of Aerosol Medicine,2001, 14(1):13-29.
[36]Hogberg S. Particle deposition in conducting airways using CFD [D]. Lulea: Lulea University of Technology,2006.
[37]Longest W, Xi JX. Computational investigation of particle inertia effects on submicron aerosol deposition in the respiratory tract [J]. Journal of Aerosol Science,2007,38:111-130.
[38]Li Z, Kleinstreuer C, et al. Simulation of airflow fields and microparticle deposition in realistic human lung airway models [J]. European Journal of Mechanics B/Fluids,2007,26:632-649.
[39]Hofmann W, et al. Simulation of three-dimensional particle deposition patterns in human lungs and comparison with experimental SPECT data [J]. Aerosol Science and Technology,2005,39:771-781.
[40]Longest W, Vinchurkar S. Effects of mesh style and grid convergence on particle deposition in bifurcating airway models with comparisons to experimental data [J].Medical Engineering & Physics,2007,29:350-366.
[41]Kleinstreuer C, Zhang Z, et al. Combined inertial and gravitational deposition of microparticles in small model airways of a human respiratory system [J]. Journal of Aerosol Science,2007,38:1047-1061.
[42]Ounis H, Ahmadi G. Analysis of dispersion of small spherical particles in a random velocity field [J]. Fluids England.1990,112:114-120.
[43]Kleinstreuer C. Biofluid dynamics—Principles and selected applications [M]. Boca Raton. FL:CRC Press,2006.
[44]Farkas A, Balashazy I. Quantification of particle deposition in asymmetrical tracheobronchial model geometry [J]. Computers in Biology and Medicine,2008, 38:508-518.
[45]Zhao Y and Lieber BB. Steady inspiratory flow in a model symmetric bifurcation [J]. ASME Journal of Biomechanical Engineering,1994,116:488-496.
[46]Liu Y, So, RMC, Zhang, CH. Modeling the bifurcating flow in a human lung airway [J]. Journal of Biomechanics,2002,35:477-485.
[47]Lippmann M. Regional deposition of particles in the human respiratory tract. In D. H. K. Lee et al. (Eds.), Handbook of physiology—reaction to environmental agents [M] Bethesda, MD:American Physiology Society,1977,213-232.
[48]Emmett PC, Aitken RJ,& Hannan WJ. Measurements of the total and regional deposition of inhaled particles in the human respiratory-tract [J]. Journal of Aerosol Science,1982,13(6):549-560.
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