Developing a tissue-engineered model of the human bronchiole

Abstract

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.