Primary Human Lung Alveolus‐on‐a‐chip Model of Intravascular Thrombosis for Assessment of Therapeutics
Abstract
Pulmonary thrombosis is a significant cause of patient mortality; however, there are no effective in vitro models of thrombi formation in human lung microvessels that could also assess therapeutics and toxicology of antithrombotic drugs. Here, we show that a microfluidic lung alveolus‐on‐a‐chip lined by human primary alveolar epithelium interfaced with endothelium and cultured under flowing whole blood can be used to perform quantitative analysis of organ‐level contributions to inflammation‐induced thrombosis. This microfluidic chip recapitulates in vivo responses, including platelet‐endothelial dynamics and revealed that lipopolysaccharide (LPS) endotoxin indirectly stimulates intravascular thrombosis by activating the alveolar epithelium, rather than acting directly on endothelium. This model is also used to analyze inhibition of endothelial activation and thrombosis due to a protease activated receptor‐1 (PAR‐1) antagonist, demonstrating its ability to dissect complex responses and identify antithrombotic therapeutics. Thus, this methodology offers a new approach to study human pathophysiology of pulmonary thrombosis and advance drug development.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 14, 2017
- Source ID
- 10.1002/cpt.742
Entities
People
- A Mammoto
- Ad Van Der Meer
- Aditya Jain
- Cs Louden
- Donald E. Ingber
- Ga Hamilton
- K De Ceunynck
- Ma Otieno
- O Aisiku
- R Barrile
- R Flaumenhaft
- T Mammoto
Organizations
- Cedars-Sinai Medical Center
- Defense Advanced Research Projects Agency
- Harvard Medical School
- Harvard University
- Janssen Pharmaceuticals
- University of Twente