Advisor: Krishnendu Roy, PhD (Biomedical Engineering)

Committee Members:

Ankur Singh, PhD (Mechanical Engineering)

Hang Lu, PhD (Chemical and Biomolecular Engineering)

Ahmet Coskun, PhD (Biomedical Engineering)

Rabin Tirouvanzium, PhD (Department of Pediatrics, Emory University)

An immune-competent microvascularized human lung-on-chip device for studying immunopathologies of the lung

Advances in microphysiological organ-on-chip technologies have enabled spatiotemporal investigation into the complex physiology of organ systems in healthy and disease-like conditions in vitro. The highly-tunable nature of on-chip models permit direct manipulation of the microenvironment and provides the framework to study disease progression in ways not feasible through other in vitro models or through in vivo animal models. Organ-on-chip models encompass cellular heterogeneity and structural organization that mimics an in vivo organ microenvironment, while still allowing for real-time, cellular-level spatial and temporal analysis. While organ-on-chip systems are becoming increasingly popular, there remains a disconnect between in vitro models of the immune system and organ-on-chip models, with very few organ-on-chips incorporating immune components. Immune dysregulation is a hallmark of nearly all disease states and thus the ability to model immune signals in vitro is paramount for the development of effective therapeutics.

We aim to address this knowledge gap through the development of an immune-competent, fully microvascularized, microfluidic human lung-on-chip device. Our overall hypotheses are (1) incorporation of tissue-resident macrophages and circulating immune cells into a lung-on-chip model will enable the recapitulation of hallmark immune dysfunction in an influenza A (H1N1) infection model and (2) development of the human lung disease model will allow identification of key drivers of disease-specific immune dysregulation and illuminate potential immunomodulatory therapies. The proposed specific aims to test these hypotheses are to (1) develop an immune-competent lung-on-chip device with tissue-resident and circulating immune populations and (2) develop and characterize viral infection in a lung-on-chip model using H1N1-induced immune activation. To date, we have demonstrated the successful incorporation of tissue-resident macrophages and circulating immune cells into a microvascularized, human lung-on-chip device. Furthermore, we have evaluated the role of tissue-resident macrophages in the immune response to H1N1 infection. Future work aims to identify key circulating immune cells involved in the response to H1N1 infection and identify potential avenues for immunomodulatory therapies. The in vitro immune response will be fully characterized using single cell RNA sequencing, flow cytometry, multiplexed cytokine analysis, and spatial-omics techniques, and the resulting information will be used to inform treatment strategies.