In Vitro Models in Chronic Obstructive Pulmonary Disease (COPD): Implications for New Diagnostic Strategies and Therapeutic Approaches.

Chronic obstructive pulmonary disease (COPD) represents a major global health issue, characterized by persistent airflow limitation, chronic inflammation, and progressive tissue remodeling. Its clinical and molecular heterogeneity, combined with the lack of resolutive therapies, underscores the urgent need for advanced experimental tools to improve understanding and therapeutic development. Traditional 2D cell culture systems, though historically useful, fail to replicate the complexity of the human lung. In this review, we analyze the remarkable relevance of advanced 3D models for studying COPD pathophysiology, including epithelial injury and regeneration, extracellular matrix remodeling, and interactions with environmental triggers such as cigarette smoke and airborne pollutants. Three-dimensional in vitro models, such as ALI cultures, lung organoids, and lung-on-a-chip platforms, PCLS, and lung ECM-derived hydrogels offer more physiologically relevant environments to investigate epithelial dysfunction, immune responses, and host-pathogen interactions. We discuss the contribution of viral and bacterial infections to COPD exacerbations, and explore how 3D models have become essential tools for modeling these events. We also highlight recent advances in personalized medicine that use patient-derived organoids and ALI cultures for drug screening and biomarker discovery. Furthermore, we examine the therapeutic potential of probiotics and extracellular vesicle-associated microRNAs to modulate inflammation and epithelial repair. Collectively, these innovative systems represent powerful platforms to promote precision medicine in COPD.