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Clin Pharmacol Ther. 2018 Feb;103(2):332-340. doi: 10.1002/cpt.742. Epub 2017 Jul 14.

Primary Human Lung Alveolus-on-a-chip Model of Intravascular Thrombosis for Assessment of Therapeutics.

Author information

1
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA.
2
Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
3
Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Biomedical Engineering, Dwight Look College of Engineering, Texas A&M University, College Station, Texas, USA.
5
Cedars-Sinai Medical Center, Los Angeles, California, USA.
6
MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
7
Janssen Pharmaceutical Research and Development, Pre-Clinical Development and Safety, Spring House, Pennsylvania, USA.
8
Emulate Inc., Boston, Massachusetts, USA.
9
Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, Massachusetts, USA.

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.

PMID:
28516446
PMCID:
PMC5693794
DOI:
10.1002/cpt.742
[Indexed for MEDLINE]
Free PMC Article

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