SUMMARYThis paper is concerned with computational modeling of the respiratory system against the background of acute lung diseases and mechanical ventilation. Conceptually, we divide the lung into two major subsystems, namely the conducting airways and the respiratory zone represented by lung parenchyma. Owing to their respective complexity, both parts are themselves out of range for a direct numerical simulation resolving all relevant length scales. Therefore, we develop detailed individual models for parts of the subsystems as a basis for novel multi-scale approaches taking into account the unresolved parts appropriately. In the tracheobronchial region, CT-based geometries up to a maximum of approximately seven generations are employed in fluid-structure interaction simulations, considering not only airway wall deformability but also the influence of surrounding lung tissue. Physiological outflow boundary conditions are derived by considering the impedance of the unresolved parts of the lung in a fully coupled 3D-1D approach. In the respiratory zone, an ensemble of alveoli representing a single ventilatory unit is modeled considering not only soft tissue behavior but also the influence of the covering surfactant film. Novel nested multi-scale procedures are then employed to simulate the dynamic behavior of lung parenchyma as a whole and local alveolar ensembles simultaneously without resolving the alveolar micro-structure completely.

The mechanical forces acting on lung parenchyma during (mechanical) ventilation and its (patho)physiological consequences are currently under intense scrutiny. Several in vivo and cell culture models have been developed to study the pulmonary responses to mechanical stretch. While providing extremely useful information, these models do also suffer from limitations in being either too complex for detailed mechanical or mechanistic studies, or in being devoid of the full complexity present in vivo (e.g., different cell types and interstitial matrix). Therefore in the present study it was our aim to develop a new model, based on the biaxial stretching of precision-cut lung slices (PCLS). Single PCLS were mounted on a thin and flexible carrier membrane of polydimethylsiloxane (PDMS) in a bioreactor, and the membrane was stretched by applying varying pressures under static conditions. Distension of the membrane-PCLS construct was modeled via finite element simulation. According to this analysis, lung tissue was stretched by up to 38% in the latitudinal and by up to 44% in the longitudinal direction, resulting in alveolar distension similar to what has been described in intact lungs. Stretch for 5 min led to increased cellular calcium levels. Lung slices were stretched dynamically with a frequency of 15/min for 4 h without causing cell injury {3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) test; live/dead straining}. These findings suggest that stretching of PCLS on PDMS-membranes may represent a useful model to investigate lung stretch in intact lung tissue in vitro for several hours.

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