Development of a human COPD model-on-a-chip to mimic disease exacerbation (a small airway-on-a-chip model)

Acute exacerbations of COPD account for the high morbidity and mortality associated with the disease. Development of pharmacotherapies for COPD has been hindered partly by the lack of appropriate in vitro disease models. Here, for the first time, we describe a biomimetic microfluidic microdevice that reconstructs the 3D mucosal lining of human small airways. Primary human airway epithelial cells from healthy normal and COPD donors were differentiated into ciliated pseudostratified epithelium in these small airway mimics. Validating the model, in line with earlier reports [Wang, R. et al. 2012; MacRedmond, R.E. et al. 2007] gene expression analysis revealed lower Toll-like Receptor (TLR)-4 transcripts in COPD compared with healthy normal. Of interest, when stimulating with TLR ligands to induce exacerbation-like phenotype, despite lower TLR levels, COPD chips mounted a more exaggerated inflammatory response. A novel aspect of the chip technology is microfluidic 'vascular' channel that allows simulation of endothelial cell-coated post-capillary venules to interrogate recruitment and attachment of circulating leukocytes. We re-created the complex organ-level response during exacerbation and compared efficacy of candidate therapeutics in modulating neutrophil adhesion to inflamed endothelium. The results demonstrated superiority of two anti-inflammatory drugs over a commonly prescribed corticosteroid in lowering neutrophilic inflammation. This new and unique technology provides the first 3D microfluidic system for modeling a human airway disease, may open path for personalized medicine, and can provide relevant feedback on efficacy and toxicity of drugs at preclinical stage.