近年來隨著空氣污染日益嚴重，其影響不僅侷限於部分地區，而是一項全球化的相關議題；它不僅造成了各地空氣品質不佳，也對人類的生命健康造成嚴重的威脅，因此對於空氣汙染顆粒在人體內沉積的情形及影響也逐漸被重視。目前為止對於顆粒在人體內沉積情形的探討大部分只侷限於模擬計算的相關研究，對於真正的顆粒沉積研究則少之又少。近年來，有學者致力於研究 “organ-on-a-chip” 技術，於體外環境模擬特定器官，重建其所包含的重要特徵。不僅可以減少實驗動物生命損失，也可以快速分析並直接獲得人體相關對應資訊，因此在我們的研究中以此為應用並提出了以可分離式的肺部呼吸模型進行粒子沉澱的研究。
在本研究中，我們改良肺模型中的第6、7、11、17及18層，並在不影響原始呼吸氣流的前提下，成功製作出了可拆解的肺模型；可拆式肺模型的優勢為對於模型中氣道的觀察可不僅只侷限於顯微鏡，還可進一步使用SEM或是LICP-MS等等的儀器做更深入的分析與研究。本實驗中，確實將模型拆開並應用於SEM的觀察。在吸入螢光粒子的研究中，首先透過螢光粒子在不同氣道條件下被吸入的實驗了解並比較其在肺部各代中的沉澱分佈情形為何，包括在模擬人類生理結構的濕潤氣道及乾燥氣道的條件下，了解到其粒子分布情形會因為氣道的條件不同有很明顯的差異存在。在濕潤氣道的條件下，發現粒子大多會因為氣道中濕潤的狀態而聚集在最上層氣道 (Z=0)，逐下明顯減少，在最後一代 (Z=4)時，幾乎不可觀察到粒子的存在，此結果似乎更符合人類因生理疾病 (例: 肺炎)而造成氣道黏液變多所至的吸入粒子沉積結果。在乾燥氣道吸入螢光粒子後並與相同條件下吸入螢光氣溶膠及文獻比較，發現其沉積結果趨勢是相似的，粒子主要沉積於前面幾代氣道，而在最後一代 (Z=4)時，粒子沉積急遽下降。另外，我們又使肺模型分別吸入二氧化鈦與飛灰粒子並打開模型以SEM觀察肺泡A1至A7後發現，因為二氧化鈦粒子較小及不易團聚的原因，而比飛灰粒子更容易沉積在肺泡的部分。在SEM的觀察下，可以觀察並歸納出不管是二氧化鈦或飛灰粒子的沉積中都可以發現三種一樣的沉積模式： (i)小粒子進入氣道後團聚成大粒子沉積 (ii)小粒子分散沉積。
雖然目前肺模型的應用尚屬於開發器官模型的初步階段，但當肺部表皮細胞導入，或是以實際空氣汙染粒子做為測試研究後，我們期許能在未來提供更深入更擬真的粒子沉積資訊。

Health deterioration by polluted air is a globe issue and a reliable model that allows one to scientifically estimate the mechanism how polluted air interacts and influences human body is thus highly desired. Recently, the great leap in the organ-on-a-chip technology precisely replicates the fine structures of lung that provides convincing results and avoid a great number of sacrifices.
In this study, we further modified the organ-on-a-chip model and made it disintegratable by changing its 6th, 7th, 11th, 17th, and 18th layer. This modification greatly facilitated for observing airborne particles depositing and distributing in the organ-on-a-chip model. Using fluorescent particles as tracers, we noted that most airborne particles in a wet airway would accumulate at the upmost layer airway (Z = 0) and there was negligible number of airborne particles found in the bottom layer airway (Z = 4). This was consistent with the clinic observation where a huge amount of airborne particles accumulated at the airway of a pneumonia patient as a result of a wet airway. In a dry airway, by contrast, airborne particles were able to penetrate into bottom layer (Z = 4). Further, airborne particles TiO2 were relatively prone to be evenly distributed in Alveolus A1 to A7 in comparison with that of airborne particles fly ash. This was because the former was relatively resistant to the aggregation. Based on our results, it was clear that the pattern when airborne particles entering in lung followed: i) aggregation of fine particles at upmost layer, ii) evenly distributed fine particles in all layers.
We expect to provide more in-depth discussions when further developed, including integration of lung epithelium cells, and also testing with the real air pollution particles in the future.

Abstract i
摘要 iii
謝致 v
Index vi
List of illustrations ix
List of tables xiv
Chapter 1. Introduction 1
1.1 Background of the study 1
1.2 Research motivation 2
Chapter 2. Literature Review 4
2.1 Human lung introduction 4
2.1.1 Pulmonary structure 4
2.1.2 Breathing mechanism of human lung 6
2.2 Air pollution particles and human lung 7
2.2.1 Current air pollution issue 7
2.2.2 Air pollutant composition and sources 7
2.2.3 Effects of air pollution particles on human lung 9
2.3 Particles deposited in the human lung 11
2.3.1 The movement of air in the human lung 11
2.3.2 The movement of particles in the human lung 12
2.3.3 Particle deposition in human lung 14
2.4 Existing lung models as studying platform 18
2.4.1 Previous studies 18
2.4.2 Limitations 20
Chapter 3. Experimental design and system fabrication 22
3.1 Design and fabrication of the separable lung device 22
3.1.1 Design of lung morphology 22
3.1.2 Design of breathing mechanism 24
3.1.3 Material selection and fabrication of the lung device 27
3.2 Breathing mechanism of lung device 30
3.2.1 Breathing system setup 30
3.2.2 Breathing flow and pattern detection 31
3.3 Particles inhalation experiments 33
3.3.1 Inhaled particle selection 33
3.3.2 Exposure system setup 36
3.3.3 Software analysis of the distribution profiles 38
Chapter 4. Current results and discussion 40
4.1 The separable lung device 40
4.1.1 The design of the separable lung device 40
4.1.2 Comparison with inseparable lung device 44
4.1.3 Breathing patterns of separable lung device 46
4.1.4 Advantages and disadvantages of the separable lung devices 48
4.2 The deposition of fluorescent particles in breathing lung device 50
4.2.1 The deposition of fluorescent particles in applied Dow Corning grease on both side lung device 50
4.2.2 The deposition of fluorescent particles in applied Dow Corning grease on right side lung device 56
4.2.3 The deposition of fluorescent particles without Dow Corning grease on lung device 66
4.2.4 The deposition of fluorescent particles in the left side large alveoli of lung device with glueA 71
4.2.5 Comparison with the results of inhalation particle experiment in lung device without Dow Corning grease 74
4.3 Deposition of TiO2 and fly ash particles in the lung device 81
4.3.1 The deposition of TiO2 particles in applied PDME glue on large alveoli lung device 82
4.3.2 The deposition of fly ash particles in applied PDME glue on large alveoli lung device 89
Chapter 5. Conclusions 93
Chapter 6. Future prospect 94
References 95

1. Weibel ER. Morphometry of the Human Lung. Springer Verlag and Academic Press, H.-N. Y.
2. Deng, Q.; Ou, C.; Chen, J.; Xiang, Y., Particle deposition in tracheobronchial airways of an infant, child and adult. Sci Total Environ 2018, 612, 339-346.
3. McWilliam, A. S.; Holt, P. G., Immunobiology of dendritic cells in the respiratory tract: steady-state and inflammatory sentinels? Toxicol Lett 1998, 102-103, 323-329.
4. Lorenz, R. J., Weibel, E. R.: Morphometry of the Human Lung. Springer Verlag, Berlin-Göttingen-Heidelberg 1963; 151 S., 109 Abb., DM 36. Biometrische Zeitschrift 1966, 8 (1‐2), 143-144.
5. Barrett, K. E., et al., Ganong's Review of Medical Physiology, 24th Edition. 2012: McGraw-Hill Education / Medical.
6. Omidvarborna, H.; Kumar, A.; Kim, D. S., Recent studies on soot modeling for diesel combustion. Renewable and Sustainable Energy Reviews 2015, 48, 635-647.
7. Esworthy, R., Air Quality: EPA's 2013 Changes to the Particulate Matter (PM) Standard 2013, (R42934), 6.
8. World Health Organization (WHO). Health effects of particulate matter. Policy implications for countries in eastern Europe, C. a. c. A. C. W. R. O. f. E.
9. Kim, K. H.; Kabir, E.; Kabir, S., A review on the human health impact of airborne particulate matter. Environment international 2015, 74, 136-43.
10. Atkinson, R. W.; Fuller, G. W.; Anderson, H. R.; Harrison, R. M.; Armstrong, B., Urban ambient particle metrics and health: a time-series analysis. Epidemiology (Cambridge, Mass.) 2010, 21 (4), 501-11.
11. Cheung, K.; Daher, N.; Kam, W.; Shafer, M. M.; Ning, Z.; Schauer, J. J.; Sioutas, C., Spatial and temporal variation of chemical composition and mass closure of ambient coarse particulate matter (PM10–2.5) in the Los Angeles area. Atmospheric Environment 2011, 45 (16), 2651-2662.
12. Srimuruganandam, B.; Shiva Nagendra, S. M., Source characterization of PM10 and PM2.5 mass using a chemical mass balance model at urban roadside. Sci Total Environ 2012, 433, 8-19.
13. Guaita et al., H. e. a., 2009; Perez et al., 2012: Samoli et al., 2008.
14. Braakhuis, H. M.; Park, M. V.; Gosens, I.; De Jong, W. H.; Cassee, F. R. J. P.; Toxicology, F., Physicochemical characteristics of nanomaterials that affect pulmonary inflammation. 2014, 11 (1), 18.
15. Guaita, R.; Pichiule, M.; Mate, T.; Linares, C.; Diaz, J., Short-term impact of particulate matter (PM(2.5)) on respiratory mortality in Madrid. International journal of environmental health research 2011, 21 (4), 260-74.
16. Organization, W. H., Air Quality Guidelines global update. 2005.
17. Carvalho, T. C.; Peters, J. I.; Williams, R. O., 3rd, Influence of particle size on regional lung deposition--what evidence is there? Int J Pharm 2011, 406 (1-2), 1-10.
18. Tippe, A.; Tsuda, A., Recirculating flow in an expanding alveolar model: Experimental evidence of flow-induced mixing of aerosols in the pulmonary acinus. 2000; Vol. 31, p 979-986.
19. Tippe, A.; Tsuda, A., Recirculating flow in an expanding alveolar model: Experimental evidence of flow-induced mixing of aerosols in the pulmonary acinus. Aerosol Science 1999, 31 (8), 979-986.
20. Fishler, R.; Hofemeier, P.; Etzion, Y.; Dubowski, Y.; Sznitman, J., Particle dynamics and deposition in true-scale pulmonary acinar models. Sci Rep 2015, 5, 11.
21. Ferron, G., Aerosol properties and lung deposition. 1994, 7 (8), 1392-1394.
22. Labiris, N. R.; Dolovich, M. B., Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. 2003, 56 (6), 588-599.
23. Nahar, K.; Gupta, N.; Gauvin, R.; Absar, S.; Patel, B.; Gupta, V.; Khademhosseini, A.; Ahsan, F., In vitro, in vivo and ex vivo models for studying particle deposition and drug absorption of inhaled pharmaceuticals. European Journal of Pharmaceutical Sciences 2013, 49 (5), 805-818.
24. Hinds, W. C., Aerosol technology: properties, behavior, and measurement of airborne particles. 2012: John Wiley & Sons.
25. United States Environmental Protection Agency, A. Q. C. f. P. M., Volume II; Environmental Protection Agency: Washington, DC, USA, 2004.
26. Mobley, C.; Hochhaus, G., Methods used to assess pulmonary deposition and absorption of drugs. Drug discovery today 2001, 6 (7), 367-375.
27. Froehlich, E.; Salar-Behzadi, S., Toxicological Assessment of Inhaled Nanoparticles: Role of in Vivo, ex Vivo, in Vitro, and in Silico Studies. 2014; Vol. 15, p 4795-822.
28. STAHLHOFEN, W.; RUDOLF, G.; JAMES, A. C., Intercomparison of Experimental Regional Aerosol Deposition Data. 1989, 2 (3), 285-308.
29. Tsuda, A.; Butler, J. P.; Fredberg, J. J., Effects of alveolated duct structure on aerosol kinetics. I. Diffusional deposition in the absence of gravity. Journal of applied physiology (Bethesda, Md. : 1985) 1994, 76 (6), 2497-509.
30. Tsuda, A., Butler, J. P. & Fredberg, J. J. Effects of alveolated duct structure on aerosol kinetics. II. Gravitational sedimentation and inertial impaction. J. Appl. Physiol. 76, 2510–2516 (1994).
31. Darquenne, C.; Paiva, M., Two- and three-dimensional simulations of aerosol transport and deposition in alveolar zone of human lung. Journal of applied physiology (Bethesda, Md. : 1985) 1996, 80 (4), 1401-14.
32. Sznitman, J.; Heimsch, T.; Wildhaber, J. H.; Tsuda, A.; Rosgen, T., Respiratory flow phenomena and gravitational deposition in a three-dimensional space-filling model of the pulmonary acinar tree. Journal of biomechanical engineering 2009, 131 (3), 031010.
33. Sznitman, J., Respiratory microflows in the pulmonary acinus. Journal of biomechanics 2013, 46 (2), 284-98.
34. Hinds, W. C., Aerosol technology : properties, behavior, and measurement of airborne particles. 2nd ed. ed.; New York (N.Y.) : Wiley: 1999.
35. Kumar, H.; Tawhai, M. H.; Hoffman, E. A.; Lin, C.-L., The effects of geometry on airflow in the acinar region of the human lung. Journal of biomechanics 2009, 42 (11), 1635-1642.
36. Fishler, R.; Ostrovski, Y.; Lu, C.-Y.; Sznitman, J., Streamline crossing: An essential mechanism for aerosol dispersion in the pulmonary acinus. Journal of biomechanics 2017, 50, 222-227.
37. Cho, S.; Yoon, J. Y., Organ-on-a-chip for assessing environmental toxicants. Current opinion in biotechnology 2017, 45, 34-42.
38. Esch, E. W.; Bahinski, A.; Huh, D., Organs-on-chips at the frontiers of drug discovery. Nature reviews. Drug discovery 2015, 14 (4), 248-60.
39. Song, Y.; Baudoin, M.; Manneville, P.; Baroud, C. N., The air-liquid flow in a microfluidic airway tree. Medical engineering & physics 2011, 33 (7), 849-56.
40. Morozov, V. N.; Kanev, I. L., Dry Lung as a Physical Model in Studies of Aerosol Deposition. Lung 2015, 193 (5), 799-804.
41. Fishler, R.; Mulligan, M. K.; Sznitman, J., Acinus-on-a-chip: a microfluidic platform for pulmonary acinar flows. Journal of biomechanics 2013, 46 (16), 2817-23.
42. Nowak, N.; Kakade, P. P.; Annapragada, A. V., Computational fluid dynamics simulation of airflow and aerosol deposition in human lungs. Ann. Biomed. Eng. 2003, 31 (4), 374-390.
43. Lambert, A. R.; O'Shaughnessy, P.; Tawhai, M. H.; Hoffman, E. A.; Lin, C.-L., Regional deposition of particles in an image-based airway model: large-eddy simulation and left-right lung ventilation asymmetry. Aerosol science and technology : the journal of the American Association for Aerosol Research 2011, 45 (1), 11-25.
44. Vestbo, J., Epidemiological studies in mucus hypersecretion. 2002; Vol. 248, p 3-19.
45. Sutera, S. P. S., R.(1993)"The history of Poiseuille's law" Annual Review of Fluid Mechanics 25:1-19.
46. Fernandez Tena, A.; Casan Clara, P., Deposition of inhaled particles in the lungs. Archivos de bronconeumologia 2012, 48 (7), 240-6.
47. Fishler, R.; Hofemeier, P.; Etzion, Y.; Dubowski, Y.; Sznitman, J., Particle dynamics and deposition in true-scale pulmonary acinar models. Sci Rep 2015, 5, 14071.
48. Pinkerton, K. E.; Green, F. H.; Saiki, C.; Vallyathan, V.; Plopper, C. G.; Gopal, V.; Hung, D.; Bahne, E. B.; Lin, S. S.; Ménache, M. G.; Schenker, M. B., Distribution of particulate matter and tissue remodeling in the human lung. Environ Health Perspect 2000, 108 (11), 1063-1069.
49. Ma, B.; Darquenne, C., Aerosol deposition characteristics in distal acinar airways under cyclic breathing conditions. Journal of applied physiology (Bethesda, Md. : 1985) 2011, 110 (5), 1271-82.