Advisor:

Shuichi Takayama, Ph.D.

Committee Members:

Rabindra Tirouvanziam, Ph.D.

Jocelyn R. Grunwell, Ph.D., MD

Andres Garcia, Ph.D.

Hang Lu, PhD

Modeling Distal Pulmonary Physiology in Microphysiological Systems

      The distal airways can become obstructed and limit lung function in many pulmonary diseases, both acute and chronic. This small airway dysfunction results from aberrant mechanical forces, inflammatory mediators, abnormal fluid properties, and other factors. However, studying these contributions to small airway disease is challenging. Existing methods, such as biopsy of human tissue, animal models, and 2D in vitro models cannot reflect the dynamic processes of fluid-mediated injury and inflammation in the small airways with adequate precision and control. Therefore, in this Thesis I develop methods to model the small airways in vitro using microphysiological systems (MPS). MPS are complex cell culture models that capture functional aspects of the tissue in a human-cell based, controlled microenvironment. Here, I utilize microfluidic platforms and high throughput culture systems to recreate phenomena that contribute to small airway injury. In Aim 1, I demonstrate that fluid-mediated injury results in small airway epithelial cell death. In Aim 2, I develop a high throughput method for generation of small airway air-blood barrier mimetic microtissues that respond to viral exposure with epithelial-endothelial coordination. Finally, in Aim 3 I apply the air-blood barrier array (ABBA) to develop a standardized, high throughput method for modeling and studying the infiltration of neutrophils into the epithelial lumen. I demonstrate the model’s disease-mimetic capability and generate patient-specific dose-response curves for anti-inflammatory therapeutics. Overall, this Thesis contributes substantially to the field of lung-mimetic microphysiological systems and contributes novel applications of such systems for the investigation of complex contributors to small airway dysfunction.