M.Sc Thesis


M.Sc StudentFriedman Lee
SubjectLung-On-Chip Platforms for Pro-Inflammatory Airway Assays
DepartmentDepartment of Biomedical Engineering
Supervisor ASSOCIATE PROF. Josue Sznitman
Full Thesis textFull thesis text - English Version


Abstract

Diseases of the respiratory system are a global leading cause of disability and mortality worldwide.  Chronic obstructive pulmonary disease is the fourth leading cause of death in the United States, exceeded only by heart attacks, cancers, and stroke.  Despite the great need, respiratory medicine appears to have only fewer new approved therapies than other common disease areas, making it the only leading cause of death that is increasing in prevalence. 

            Animal experiments have contributed much to our understanding of disease physiology and are commonly used to estimate the safety and effectiveness of new therapies before clinical trials are carried out.  However, animal models of the respiratory diseases do not translate straightforwardly to humans due to significant differences in their immune system development, activation, and response to inflammatory triggers, in both the innate and adaptive arms.  For example, discrepancies between mouse models and humans include among others: balance of leukocytes subsets, Toll receptors, monocytes differentiation, types of cytokines secreted, the expressed cytokine receptors, etc. The aforementioned limitations raise an immense need for designing pre-clinical in vitro platforms that would circumvent, or at the very least reduce, the ongoing use of animal studies. 

            Therefore, in the study presented here, we aim to develop a human cell-based microfluidic device that mimics inflammatory characteristics of the acinar region.  Specifically, a triple co-culture in vitro cell model lined with a human alveolar epithelial lentivirus cell line (hAELVi), human differentiated monocytic cell line (THP-1), and a human neutrophil-like cell line (U937) to recapitulate elements of viral and bacterial local inflammation within the microfluidic acini-on-chip model.  We exposed the cell co-culture model to the well-established inflammatory stimulators: polyinosinic:polycytidylic acid (poly I:C) and lipopolysaccharide (LPS).  Of significance, two characteristics identified with local inflammation were observed after the viral and bacterial exposure: an increase in the concentration of pro-inflammatory cytokines in conjunction with the transmigration of immune cells to the inflamed region at the airway’s air-liquid interface.  Altogether, the presented microfluidic device may offer a better platform for recapitulating with sufficient accuracy the acinar local inflammation and potentially serve as an advanced platform for pulmonary drug screening in preclinical trials.