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Development of lung on a chip for mimicking particulate matter exposure conditions

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Abstract
The Drug discovery process takes decades to bring a new drug to the market,preclinical animal models based drug testing results in failure of 90% drugs due to drugtoxicity and inefficacy. A preclinical study of a lead compound goes through 2D cultures andanimal testing to study Pharmacodynamics and pharmacokinetics for before clinical testing.Safety and efficacy of a lead compound may not be accurately predicted by utilizing thesepreclinical models. Preclinical phase and screening in Drug development needs morerelevant models of human organ systems to avoid failures. Organ-on-chip technology isoffering physiologically relevant human organ models to replace animal testing for betteranalysis of drugs, environmental toxins (Xenobiotics) and food testing. Organ levelcomplexity is an obstacle to study human airway diseases and in the development of newtherapeutics for Asthma and COPD. Particulate matter (PM10) induced respiratory illnessesare a challenge to study in trans-well culture system. Micro-physiological systems offerpotential for mimicking these phenomena for better understanding of possible hazards tohuman respiratory health. Here we have developed Human Lung, Lung cancer, on amicrofluidic chip equipped with a peristaltic pump, real-time microscope and systemintegrated pH, TEER, Dissolved Oxygen provided patho-physiologically relevant human data.The Patho-physiological significance of the human organ mimetics was well characterized byconfocal laser scanning microscopy, ELISA and TEER sensor. A Highly efficient organ-on-chipdevice can perform high throughput drug screening analysis with accurately mimickinghuman physiology. The Special focus of the study was testing particulate matter (PM<10) indynamic conditions on a microfluidic chip. Human lung distal airway models releasecytokines and in large quantities, as compared to the 2D static cultures. Environmental conditions with respect to particulate matter in air Mild 7.5μg/ml, Average 37.5μg/ml andpoor 151μg/ml of particulate matter exposure was executed in our microfluidic system. Ourstudy provides physiological and toxicological data of the stimulated environmentalcondition by inflammatory markers of respiratory disease, which leads to the identificationof asthma and chronic obstructive pulmonary disease. The claims were validated byconfocal microscopy and ELISA. Significant increase in IL-13, IL-6 and MUC-5AC advocatedthe incidence of asthma and chronic obstructive pulmonary disease conditions in ournormal and cancer chips. This work will lead to the identification of potential therapeuticsand prevention of chronic life-threatening toxicities. The future direction of the work is tomoves towards multi-organ on a chip to study the effects of drugs on the liver and otherinterconnects organs for providing better clinically relevant human models
Author(s)
Faiza Jabbar
Issued Date
2021
Awarded Date
2021. 2
Type
Dissertation
URI
https://oak.jejunu.ac.kr/handle/2020.oak/23487
Affiliation
제주대학교 대학원
Department
대학원 에너지응용시스템학부 Mechatronics Engineering
Advisor
Choi, Kyung Hyun
Table Of Contents
Abstract. 1
Introduction 3
2. Particulate matter and organ on a chip 5
2.1 Organ on chip technology . 14
2.2. Role of Microfluidics in Organ on chip technology 14
2.4 Physio-pathologically relevant human organ models 17
2.4.1 Lung on chip. 17
2.4.2 Liver-on-a-chip. 21
2.4.3 Kidney on chip 24
2.5 Particulate matter based models 26
3. Materials & Methods 32
3.1 Materials: 32
3.2 Methods 34
3.2.1 Microfluidic chip fabrication 34
3.3 Microscope development & Sensor development. 35
3.4 Microfluidic cell culture 37
3.4.1 Microfluidic cell culture maintenance of lung on chip 37
3.5 Human organs on chip models development. 38
3.5.1 Lung on a chip 38
3.5.2 Pathological models development 41
3.5.3 Exposure scheme of fine dust 41
3.6 Toxicity analysis. 41
3.6. 1 Determination of Membrane barrier integrity: 41
3.6.2 Immunofluorescence Analysis of compromised barrier integrity. 42
3.6.3 Analysis of cytokines release and ROS representing diseased conditions 42
3.7 DCFDA assay for ROS analysis. 44
4. Results. 44
4.1 Characterization of Particulate matter. 44
4.2 Impedance data demonstrating barrier integrity: 46
4.3 Monolayer Membrane integrity epithelium barrier properties. 48
4.4 Compromised barrier integrity upon particulate matter exposure . 48
4.5 Confocal imaging of Goblet cell hyperplasia and ciliated cells dysfunction . 49
4.6 Confocal imaging of the Cancer invasion in Asthmatic lung. 53
4.7 ROS estimation 54
4.8 Cytokine release analysis 56
5. Discussion 61
Conclusion. 64
References. 66
Degree
Doctor
Publisher
제주대학교 대학원
Citation
Faiza Jabbar. (2021). Development of lung on a chip for mimicking particulate matter exposure conditions
Appears in Collections:
Faculty of Applied Energy System > Mechatronics Engineering
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