Acoustically detectable cellular-level lung injury induced by fluid mechanical stresses in microfluidic airway systems

Departments of *Biomedical Engineering and
^¶Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI 48109-2099; and
^‡Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105

Edited by Howard A. Stone, Harvard University, Cambridge, MA, and accepted by the Editorial Board September 10, 2007 (received for review December 7, 2006)

Abstract

We describe a microfabricated airway system integrated with computerized air–liquid two-phase microfluidics that enables on-chip engineering of human airway epithelia and precise reproduction of physiologic or pathologic liquid plug flows found in the respiratory system. Using this device, we demonstrate cellular-level lung injury under flow conditions that cause symptoms characteristic of a wide range of pulmonary diseases. Specifically, propagation and rupture of liquid plugs that simulate surfactant-deficient reopening of closed airways lead to significant injury of small airway epithelial cells by generating deleterious fluid mechanical stresses. We also show that the explosive pressure waves produced by plug rupture enable detection of the mechanical cellular injury as crackling sounds.

Footnotes

^∥To whom correspondence should be addressed at:
Department of Biomedical Engineering, University of Michigan, 2200 Bonisteel Boulevard, 2115 Gerstacker, Ann Arbor, MI 48109-2099.
E-mail: takayama{at}umich.edu
Author contributions: D.H., R.P., J.B.G., and S.T. designed research; D.H. performed research; H.F., Y.-C.T., N.F., and J.B.G. contributed new reagents/analytic tools; D.H., H.F., Y.-C.T., J.B.G., and S.T. analyzed data; and D.H. and S.T. wrote the paper.
↵ ^†Present address: Vascular Biology Program, Departments of Pathology and Surgery, Harvard Medical School and Children's Hospital, Boston, MA 02115.
↵ ^§Present address: Department of Internal Medicine and Division of Pulmonary and Critical Care Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. H.A.S. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/cgi/content/full/0610868104/DC1.