建立循環呼吸模型以應用於吸入型藥物之開發

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研究生：	林雋凱 Lin, Chun-Kai
論文名稱：	建立循環呼吸模型以應用於吸入型藥物之開發 Construction of in vitro Human Breathing Lung Model for Inhalation Drug Development
指導教授：	黃振煌 Huang, Jen-Huang
口試委員:	王竹方姜文軒
學位類別：	碩士 Master
系所名稱：	工學院 - 化學工程學系 Department of Chemical Engineering
論文出版年：	2018
畢業學年度：	106
語文別：	英文
論文頁數：	68
中文關鍵詞：	微流道製造技術、仿肺部裝置、疾病模型、震動篩版式霧化器、螢光氣溶膠沉積、氣溶膠分布情形
外文關鍵詞：	Microfabrication technique, Lung device, Disease model, Vibrating mesh nebulizer, Fluorescein aerosol deposition, Aerosol distribution profile
相關次數：	點閱：3 下載：0
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藥物開發階段往往使用動物實驗，但就許多方面而言，都被證實效率不佳。一些通過臨床測試階段的藥物，之後被發現於人體中產生副作用，造成不必要的損失，產生法律上的責任，甚至更嚴重，病人的死亡。因此近年來，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。其不僅可以減少實驗動物生命損失，也能加快藥物開發時程並直接獲得人體相關對應資訊。這些模型或裝置可以應用於觀測藥物於人體特定器官中的吸收，分布情況，代謝表現，分解或是毒性反應(ADMET)。然而，應用於吸入型藥物的肺部模型中，目前只存在少許的模型同時具有結構特徵以及呼吸表現。
因此於本項研究中，透過設計與參數調整，我們逐漸建立起一個多層結合的肺部裝置，包含與成人肺部相似的15至19代支氣管結構，以及具有呼吸功能的肺泡囊區域。重建肺部特色模型並非不切實際，當能達到生理結構及表現上的相似性，我們可以進一步探討目標藥物於模擬區域的分布情況與藥物動力學特色，我們期許能提供值得信賴的臨床醫學資訊，使藥物開發過程更有效率，能更快速進入人體實驗階段。於本研究的後段實驗中，我們也模擬了不同的類疾病模型，包刮阻塞型(obstructive)及限制型(restrictive)疾病，並探討螢光氣溶膠於氣體管道中的分布情形。然而目前尚屬於開發器官模型的初步階段，當肺部表皮細胞導入，或是測試不同市售藥物後(包含氣霧式，乾粉式等等)，我們期許能在未來提供更深入的臨床醫學資訊。

Drug discovery through animal testing has been proven inefficient in many instances. Even some pharmaceuticals that successfully passed clinical trials are later found to have serious side effects that can lead to unwanted suffering, costly lawsuits, or even worse, the death of patients. Reconstructing human organ features in an artificial model, known as“organ-on-a-chip”, not only helps prevent life loss of experimental animals but also provides a reliable human physiological response if thoroughly developed. These in vitro models have been used to study the absorption, distribution, metabolism, elimination (ADMET), and toxicity of drugs. However, in the field of inhalable drug development, there are only a few such models that both integrate regional lung geometry and breathing motion.
In this study, we developed a stepwise approach to construct a multi-layered breathing lung device that integrates both branched morphology (focusing on the 15th to the 19th generation of the human lung) and deformable alveolar features. It is not trivial to emulate the physiological performance of human lung, while physiological structure and pharmacokinetic behaviors have to be well known in order to produce reliable medical information. Our results provide a preliminary conceptual framework of aerosol distribution profile under various pulmonary breathing models at this stage, and we expect to provide more in-depth discussions when further developed, including integration of lung epithelium cells, and also testing with commercially available drugs (such as nebulized or powdered form drug) in the future.

Abstract...........................................................i
摘要..............................................................ii
Acknowledgments..................................................iii
Contents..........................................................iv
List of illustrations............................................vii
List of tables.....................................................x
Chapter 1. Introduction of pulmonary features and in vitro studies.1
1 Prevailing lung diseases and air pollution problems............1
1.1 Obstructive lung diseases....................................2
1.3 Restrictive lung diseases....................................2
1.3 Air pollution issue..........................................3
2 Pulmonary administration.......................................4
3 Existing lung models as studying platform......................6
3.1 Previous studies.............................................6
3.2 Limitations..................................................8
4 Human lung introduction........................................9
4.1 Structure features..........................................10
4.2 Breathing mechanism.........................................11
4.3 Particle distribution and flow features.....................11
5 Construction of cyclic breathing lung device..................12
5.1 Lung morphology design concept..............................12
5.2 Breathing motions induced by deformable PDMS membrane.......13
5.3 Polydispersed aerosol for exposure assays...................14
6 Purpose.......................................................15
Chapter 2. Experimental design and system fabrication.............17
1 Computer-assisted design (CAD)................................17
1.1 Design of lung morphology...................................18
1.2 Design of breathing mechanism...............................19
2. Material selection and fabrication of the lung device........22
2.1 PMMA........................................................22
2.2 PET.........................................................23
2.3 Fabrication of PDMS membrane................................23
2.4 Fabrication of lung device..................................24
3 Fabrication of system.........................................26
3.1 Breathing system setup......................................27
3.2 Exposure system setup.......................................28
4 Breathing flow and pattern detection..........................30
5 Aerosol deposition assay......................................33
5.1 Aerosol deposition on targeted materials....................33
5.2 Aerosol deposition in lung device...........................34
6 Software analysis of the distribution profiles................37
7 Design and fabrication of the separable lung device...........38
Chapter 3. Current results and discussion.........................40
1 Design of the breathing lung device...........................40
2 PDMS membrane fabrication.....................................42
3 Flow rate selection...........................................45
3.1 Peristaltic pump flow rate..................................45
3.2 PEEK tubing restriction flow pressure drop..................46
4 Breathing flow investigation and pattern detection............47
5 Aerosol deposition pre-test...................................50
5.1 Aerosol deposition on targeted materials....................51
5.2 Humid chamber exposure of lung device.......................52
6 Aerosol deposition test.......................................53
6.1 Distribution profile under moderate breathing condition.....54
6.2 Distribution profile under disease-like breathing models....56
6.3 Distribution profile under other breathing conditions.......57
7 Separable lung device.........................................58
7.1 Breathing patterns of separable lung device.................59
7.2 Future application: DPI study...............................60
1 Conclusions...................................................62
2 Future prospects..............................................63
Reference.........................................................64


                                

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