ABSTRACT
Motivated by a desire to uncover new opportunities for designing the size and shape of fiber-shaped aerosols towards improved pulmonary drug delivery deposition outcomes, we explore the transport and deposition characteristics of fibers under physiologically inspired inhalation conditions in silico, mimicking a dry powder inhaler (DPI) maneuver in adult lung models. Here, using computational fluid dynamics (CFD) simulations, we resolve the transient translational and rotational motion of inhaled micron-sized ellipsoid particles under the influence of aerodynamic (i.e., drag, lift) and gravitational forces in a respiratory tract model spanning the first seven bifurcating generations (i.e., from the mouth to upper airways), coupled to a more distal airway model representing nine generations of the mid-bronchial tree. Aerosol deposition efficiencies are quantified as a function of the equivalent diameter (dp) and geometrical aspect ratio (AR), and these are compared to outcomes with traditional spherical particles of equivalent mass. Our results help elucidate how deposition patterns are intimately coupled to dp and AR, whereby high AR fibers in the narrow range of dp = 6-7 µm yield the highest deposition efficiency for targeting the upper- and mid-bronchi, whereas fibers in the range of dp= 4-6 µm are anticipated to cross through the conducting regions and reach the deeper lung regions. Our efforts underscore previously uncovered opportunities to design the shape and size of fiber-like aerosols towards targeted pulmonary drug delivery with increased deposition efficiencies, in particular by leveraging their large payloads for deep lung deposition.
ABSTRACT
Non-spherical particles, and fibers in particular, are potentially attractive airborne carriers for pulmonary drug delivery. Not only do they exhibit a high surface-to-volume ratio relative to spherical aerosols, but their aerodynamic properties also enable them to reach deep into the lungs. Until present, however, our understanding of the deposition characteristics of inhaled aerosols in the distal acinar lung regions has been mostly limited to spheres. To shed light on the fate of elongated aerosols in the pulmonary depths, we explore through in silico numerical simulations the deposition and dispersion characteristics of ellipsoid-shaped fibers in a physiologically-realistic acinar geometry under oscillatory breathing flow conditions mimicking various inhalation maneuvers. The transient translation and rotational movement of micron-sized elongated particles under drag, lift, and gravitational forces are simulated as a function of size (dp) and aspect ratio (AR). Our findings underscore how acinar deposition characteristics are intimately linked to the geometrical combination of dp and AR under oscillatory flow conditions. Surprisingly, the elongation of the traditionally recommended size range of spherical particles (i.e., 2-3⯵m) for acinar deposition may lead to a decrease in deposition efficiency and dispersion. Instead, our findings advocate how elongating particles (i.e., high AR) in the larger size range of 4-6⯵m might be leveraged for improved targeted deposition to the acinar regions. Together, these results point to new windows of opportunities in selecting the shape and size of micron-sized fibers for targeted pulmonary deposition. Such in silico efforts represent an essential stepping stone in further exploring aerosol drug carrier designs for inhalation therapy to the deep lungs.
Subject(s)
Drug Carriers/administration & dosage , Models, Biological , Pulmonary Alveoli/metabolism , Administration, Inhalation , Aerosols/administration & dosage , Computer SimulationABSTRACT
It is widely acknowledged that inhaled fibers, e.g. air pollutants and anthropogenic particulate matter, hold the ability to deposit deep into the lungs reaching the distal pulmonary acinar airways as a result of their aerodynamic properties; these particles tend to align with the flow and thus stay longer airborne relative to their spherical counterpart, due to higher drag forces that resist sedimentation. Together with a high surface-to-volume ratio, such characteristics may render non-spherical particles, and fibers in particular, potentially attractive airborne carriers for drug delivery. Until present, however, our understanding of the dynamics of inhaled aerosols in the distal regions of the lungs has been mostly limited to spherical particles. In an effort to unravel the fate of non-spherical aerosols in the pulmonary depths, we explore through numerical simulations the kinematics of ellipsoid-shaped fibers in a toy model of a straight pipe as a first step towards understanding particle dynamics in more intricate acinar geometries. Transient translational and rotational motions of micron-sized ellipsoid particles are simulated as a function of aspect ratio (AR) for laminar oscillatory shear flows mimicking various inhalation maneuvers under the influence of aerodynamic (i.e. drag and lift) and gravitational forces. We quantify transport and deposition metrics for such fibers, including residence time and penetration depth, compared with spherical particles of equivalent mass. Our findings underscore how deposition depth is largely independent of AR under oscillatory conditions, in contrast with previous works where AR was found to influence deposition depth under steady inspiratory flow. Overall, our efforts underline the importance of modeling oscillatory breathing when predicting fiber deposition in the distal lungs, as they are inhaled and exhaled during a full inspiratory cycle. Such physical insight helps further explore the potential of fiber particles as attractive carriers for deep airway targeting.
Subject(s)
Aerosols/chemistry , Computer Simulation , Drug Delivery Systems/methods , Hydrodynamics , Laryngeal Masks , Powders/chemistry , Administration, Inhalation , Biomechanical Phenomena , Chemistry, Pharmaceutical/methods , Humans , Lung , Models, Biological , Motion , Nebulizers and Vaporizers , Particle Size , Permeability , Pulmonary Alveoli/drug effects , Respiration , Respiratory Tract AbsorptionABSTRACT
Diffusional screening in the lungs is a physical phenomenon where the specific topological arrangement of alveolated airways of the respiratory region leads to a depletion, or 'screening', of oxygen molecules with increasing acinar generation. Here, we revisit diffusional screening phenomena in anatomically-inspired pulmonary acinar models under realistic breathing maneuvers. By modelling 3D bifurcating alveolated airways capturing both convection and diffusion, unsteady oxygen transport is investigated under cyclic breathing motion. To evaluate screening characteristics in the developing lungs during growth, four representative stages of lung development were chosen (i.e. 3 months, 1 year and 9 months, 3 years and adulthood) that capture distinct morphological acinar changes spanning alveolarization phases to isotropic alveolar growth. Numerical simulations unveil the dramatic changes in O2 transport occurring during lung development, where young infants exhibit highest acinar efficiencies that rapidly converge with age to predictions at adulthood. With increased ventilatory effort, transient dynamics of oxygen transport is fundamentally altered compared to tidal breathing and emphasizes the augmented role of convection. Resolving the complex convective acinar flow patterns in 3D acinar trees allows for the first time a spatially-localized and time-resolved characterization of oxygen transport in the pulmonary acinus, from infancy to adulthood.