Engineered Airway Models to Study Liquid Plug Splitting at Bifurcations: Effects of Orientation and Airway Size.

Delivery of biological fluids, such as surfactant solutions, into lungs is a major strategy to treat respiratory disorders including respiratory distress syndrome that is caused by insufficient or dysfunctional natural lung surfactant. The instilled solution forms liquid plugs in lung airways. The plugs propagate downstream in airways by inspired air or ventilation, continuously split at airway bifurcations to smaller daughter plugs, simultaneously lose mass from their trailing menisci, and eventually rupture. A uniform distribution of the instilled biofluid in lung airways is expected to increase the treatments success. The uniformity of distribution of instilled liquid in the lungs greatly depends on the splitting of liquid plugs between daughter airways, especially in the first few generations from which airways of different lobes of lungs emerge. To mechanistically understand this process, we developed a bioengineering approach to computationally design three-dimensional bifurcating airway models using morphometric data of human lungs, fabricate physical models, and examine dynamics of liquid plug splitting. We found that orientation of bifurcating airways has a major effect on the splitting of liquid plugs between daughter airways. Changing the relative gravitational orientation of daughter tubes with respect to the horizontal plane caused a more asymmetric splitting of liquid plugs. Increasing the propagation speed of plugs partially counteracted this effect. Using airway models of smaller dimensions reduced the asymmetry of plug splitting. This work provides a step toward developing delivery strategies for uniform distribution of therapeutic fluids in the lungs.

A Three-Dimensional Model of Human Lung Airway Tree to Study Therapeutics Delivery in the Lungs.

Surfactant instillation into the lungs is used to treat several respiratory disorders such as neonatal respiratory distress syndrome (NRDS). The success of the treatments significantly depends on the uniformity of distribution of the instilled surfactant in airways. This is challenging to directly evaluate due to the inaccessibility of lung airways and great difficulty with imaging them. To tackle this problem, we developed a 3D physical model of human lung airway tree. Using a defined set of principles, we first generated computational models of eight generations of neonates' tracheobronchial tree comprising the conducting zone airways. Similar to native lungs, these models contained continuously-branching airways that rotated in the 3D space and reduced in size with increase in the generation number. Then, we used additive manufacturing to generate physical airway tree models that precisely replicated the computational designs. We demonstrated the utility of the physical models to study surfactant delivery in the lungs and showed the effect of orientation of the airway tree in the gravitational field on the distribution of instilled surfactant between the left and right lungs and within each lung. Our 3D lung airway tree model offers a novel tool for quantitative studies of therapeutics delivery.