Research database

Pulmonary fibrosis (PF) is a lung disease characterized by the progressive impairment of lung function and poor prognosis, with an estimated median survival of 2–3 years from the time of diagnosis. Recently, the correlation between long-term exposure to harmful substances that damage the lungs, such as tobacco smoke, air pollution, and certain occupational chemicals, and PF progress has emerged. However, there is lack of evidence on the pollutant potential role on the onset of PF and the resulting devastating events. Therefore, there is an urgent need for relevant in vitro models that can capture fundamental aspects of lung physiology and pathology and replicate the irritants deposition and distribution after pollutants exposure. BREATH proposes a bioengineering in vitro strategy based on the manufacturing of a 3D bioprinted alveolar lung-on-chip (ALOC) platform, to successfully reproduce the curved microstructure, the native extra cellular matrix (ECM) function, the differentiated epithelium at the air–liquid interface (ALI), and the breathing events of the pulmonary alveoli, which are the basic units enabling gas exchanges in the human lung. To fulfill this goal, the three Research Unit (RUs) involved in BREATH will: (i) perform an epidemiological analysis to select specific pollutants responsible for PF onset, which will be pre-screened onto an optimized 2.5D in vitro lung model; (ii) design and manufacture a 3D acinar microenvironment with residing curved alveolar sacs, by Freeform Reversible Embedding of Suspended Hydrogels (FRESH) 3D extrusion bioprinting, which will be integrated into a PDMS-based microfluidic organ-on-chip device to reproduce the ALI and the cyclic inhalation/exhalation movements, to simulate the breathing process; (iii) expose the ALOC to single or multiple external insults, by using nanoparticles-loaded aerosol, with the aim of mimicking the physiological inhalation conditions of PF disease etiology. PF key events including inflammation, aberrant epithelial repair, impaired barrier integrity, dysregulated fibroblast activity and transdifferentiation will be quantitively measured by means of established assays. Within BREATH, via the combination of bioprinting and organ-on-chip technologies, our model will provide a useful tool for mimicking physiological inhalation condition and in situ-like deposition. The outcomes will help predict inflammation severity upon inhalation exposure of pollutants, thus increasing the knowledge on PF onset and the effect of lung exposure to specific pollutants. In a long term perpspective, the platform should facilitate the safety assessment of chemicals, as well as the development and efficacy testing of innovative drugs, as the recent pandemic also highlighted. Thus, satisfying the EU requests that push towards the development of suitable alternatives and for the full implementation of the 3R’s principles (Replacement, Reduction and Refinement of Animal Testing).