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RESEARCH ARTICLE JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE J Tissue Eng Regen Med (2010). Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/term.277

Developing a tissue-engineered model of the human bronchiole

C h e r y l M i l l e r 1 * , S t e v e n G e o r g e 2 a n d L a u r a N i k l a s o n 3

1 2 3

Department of Biomedical Engineering, St. Louis University, St. Louis, MO 63103, USA Department of Biomedical Engineering, University of California at Irvine, Irvine, CA 92697, USA Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA


Scientists are always looking for new tools to better mimic human anatomy and physiology, especially to study chronic respiratory disease. Airway remodelling is a predominant feature in asthma and occurs in conjunction with chronic airway inflammation. Both the inflammatory and repair processes alter the airway wall which is marked by anatomical, physiological and functional changes. A tissue-engineered model of bronchiole remodelling presents a novel approach to investigating the initiation and progression of airway remodelling. By developing a unique bioreactor system, cylindrical-shaped bronchioles constructed from well-characterized human lung primary cells have been engineered and examined with a much greater control over experimental variables. We have grown human bronchioles composed of fibroblasts, airway smooth muscle cells, small airway epithelial cells and extracellular matrices. The various cell types are in close proximity to one another for cell–cell signalling and matrix interactions. The cylindrical geometry of the tissue applies radial distension for mechanotransduction and the air interface provides a natural environment for the epithelial cells. Optimal cell density, extracellular matrix concentration and media composition were determined. Immunohistochemistry verified bronchiole phenotypic stability. Quiescence was gauged by protein expression which verified a change in phenotype after the initial fabrication stage and implementation of the air interface. A fabrication timeline was devised for repeatable bronchiole fabrication and to understand tissue contraction and cell- seeding duration. The stability of the bronchiole structures and their cellular composition lends these bronchioles to study cell–cell interactions and remodelling events while maintaining in vivo geometrical dimensions and relationships. Copyright 2010 John Wiley & Sons, Ltd.

Received 8 July 2009; Accepted 25 February 2010

Keywords tissue engineering; bioreactor; bronchioles; phenotype; fibroblasts; bronchiole epithelial cells; airway smooth muscle cells



1. Introduction

Although substantial progress has been made in the study of airway remodelling, the initiation and progression of chronic respiratory disease is not well understood, due to its dynamic nature in vivo. A tissue-engineered model of the bronchioles is a potentially powerful approach to studying airway remodelling, as cell–cell and cell–matrix interactions can be considered. Indeed, several models of the airway wall have been developed to investigate

*Correspondence to: Cheryl Miller, 3507 Lindell Boulevard, St. Louis, MO 63103, USA. E-mail: cmille42@slu.edu

epithelial–stromal communication (Tschumperlin and Drazen, 2001; Agarwal et al., 2003; Choe et al., 2006), but none have incorporated the native cylindrical geometry of the in vivo bronchiole nor both fibroblasts and smooth muscle cells. Furthermore, tissue engineering has recently been proposed as an important avenue to understanding tissue physiology, as opposed to solely developing tissues for implantation or replacement (Griffith and Swartz, 2006).

As an experimental model to investigate airway remodelling, we have developed a bioreactor system to fabricate cylindrical airways, which maintains the bronchioles under mechanical stimulation and humidified

Copyright 2010 John Wiley & Sons, Ltd.

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