74 Chapter 4 INTRODUCTION Chronic lung diseases contribute significantly to the global burden of healthcare [1]. Asthma, chronic obstructive pulmonary disease (COPD), lung fibrosis, pulmonary hypertension, and lung cancer are some common examples [1]. Structural alterations and cellular damage in these chronic diseases can be the result of (combinations of) prolonged exposure to environmental factors such as smoke (cigarette or other sources), air pollution, and pathogens or genetic predisposition [2]. As a result, chronic diseases are often characterised by excessive mucus secretion [3, 4], reduced mucociliary clearance [3, 4], and aberrant remodelling of the airways, pulmonary vasculature and distal parenchymal tissue [5]. Subsequently, airflow limitation and alveolar tissue destruction results in the loss of lung function [3-5]. Localised repair and regeneration in the lung can be facilitated by resident progenitor cells [2, 6], but these progenitor cells can be functionally impaired in disease conditions [6]. Therefore, for most end-stage lung diseases, the only definitive treatment is lung transplantation [7]. Developing appropriate treatments for chronic lung diseases can be bolstered through thorough understanding of disease mechanisms. In spite of the abundance and advancement in knowledge, the pathogenesis and progression of most chronic diseases remains unclear. Much knowledge has been obtained from rodent studies, which often do not completely recapitulate human diseases [8]. Traditional two dimensional (2D) in vitro cell culture approaches have played a fundamental role in advancement of current knowledge of cell behaviour and fate. However, these approaches lack a range of essential cell-cell and cell-extracellular matrix (ECM) interactions that have been shown to define cell signalling and function [9]. Bioengineering has promoted the development of innovative in vitro systems for modelling diseases in lung research [10]. Hence, three-dimensional (3D) models containing one or more matrix components and multiple cell types are becoming the sought-after standard for in vitro studies. These models support the growth of cells in all directions and allow for interaction with their surroundings. The use of models emulating human disease will not only aid in increased understanding of disease processes, but new models can also improve the drug development process and safety testing. This review extensively describes the state-of-the-art for in vitro models developed for ex vivo engineering in lung research as a summary and postscript of the presentations and discussions that took place during the European Respiratory Society (ERS) Research Seminar: “Innovative 3D models for understanding mechanisms underlying lung diseases: powerful tools for translational research” in Lisbon, Portugal in April 2022. A synopsis of various traditional and novel methods for characterisation of these
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