Advanced compartmentalized lung-on-chip to investigate the cross-talk of two entities; Pulmonary Arterial Hypertension and Emphysema

• Applicant: Ali Doryab, Ph.D.
• Subject Area: Pneumology, Thoracic Surgery ; Biomaterials ; Biomedical Systems Technology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 524039583

In this project, I intend to develop the first human-based compartmentalized lung-on-chip to resemble alveolar-capillary and pulmonary vasculature regions. The compartmentalized lung-on-chip consists of a pulmonary blood vessel-on-chip linked to an alveolus-on-chip to study cross-talk between one of the significant lung comorbidities, i.e., pulmonary arterial hypertension (PAH) and emphysema. As part of this endeavor, I will integrate advanced vascular and alveolar cell models based on primary human tissue-specific cells into the chips to better emulate the characteristics and functions of the in vivo counterpart. With this lung-on-chip, I will explore the interplay between PAH and lung emphysema. I have selected four primary goals for this project, as I outline below. My first goal is to fabricate a co-culture pulmonary blood vessel-on-chip consisting of primary human pulmonary microvascular endothelial and human pulmonary artery smooth muscle cells. On this chip, PAH will be induced by applying non-physiologic shear stress to the endothelial cells under hypoxia. The PAH-on-chip will be validated by the measurement of pathological markers of PAH. My second goal is to develop a complex triple co-culture alveolus-on-chip. The barrier integrity and specific markers of epithelial, fibroblast, and endothelial cells will be assessed under clinically relevant dynamic conditions (physiologic cyclic mechanical stretch and shear stress). This chip will be turned into an emphysema-on-chip by exposing the cells to elastase. Analogous to the PAH-on-chip, the emphysema-on-chip will be characterized by emphysema-specific pathological markers. As my third goal, I will connect the vessel-on-chip to the alveolus-on-chip using a perfusion loop (via culture medium in the basal chamber) to establish the vessel-alveolus-on-chip compartmental lung model, mimicking the complex compartmentation of the three-dimensional lung. The operating conditions will have to be optimized for the co-culturing of both types of chips in an interconnected perfusion system. My fourth goal is to leverage this two-linked-chip model to investigate a potential causal interplay of the progression of PAH and pulmonary emphysema. This goal is subdivided into two aspects, namely, unraveling the role of PAH in inducing pulmonary emphysema and vice versa. Thus, I will first connect the PAH-on-chip to the (healthy) alveolus-on-chip model and monitor the potential induction of emphysema features such as inflammatory responses, cell apoptosis, and barrier leakage. Then, I will connect the emphysema-on-chip to the (healthy) vessel-on-chip model to investigate the potential instigation of PAH features. The inflammatory responses, cell apoptosis, smooth muscle cell proliferation, and arrangement /proliferation of ECM proteins will be analyzed as pathological hallmarks of PAH. The overall objective of this project is to pave the way for in vitro investigation of lung-centered co-morbidities.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Dr. Donald E. Ingber