Three-dimensional models of the lung: past, present and future: a mini review.

Respiratory diseases are a major reason for death in both men and women worldwide. The development of therapies for these diseases has been slow and the lack of relevant human models to understand lung biology inhibits therapeutic discovery. The lungs are structurally and functionally complex with many different cell types which makes designing relevant lung models particularly challenging. The traditional two-dimensional (2D) cell line cultures are, therefore, not a very accurate representation of the in vivo lung tissue. The recent development of three-dimensional (3D) co-culture systems, popularly known as organoids/spheroids, aims to bridge the gap between 'in-dish' and 'in-tissue' cell behavior. These 3D cultures are modeling systems that are widely divergent in terms of culturing techniques (bottom-up/top-down) that can be developed from stem cells (adult/embryonic/pluripotent stem cells), primary cells or from two or more types of cells, to build a co-culture system. Lung 3D models have diverse applications including the understanding of lung development, lung regeneration, disease modeling, compound screening, and personalized medicine. In this review, we discuss the different techniques currently being used to generate 3D models and their associated cellular and biological materials. We further detail the potential applications of lung 3D cultures for disease modeling and advances in throughput for drug screening.