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. 2020 Mar 5;12(3):230.
doi: 10.3390/pharmaceutics12030230.

In Silico Optimization of Fiber-Shaped Aerosols in Inhalation Therapy for Augmented Targeting and Deposition Across the Respiratory Tract

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Free PMC article

In Silico Optimization of Fiber-Shaped Aerosols in Inhalation Therapy for Augmented Targeting and Deposition Across the Respiratory Tract

Lihi Shachar-Berman et al. Pharmaceutics. .
Free PMC article

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.

Keywords: aerosols; computational fluid dynamics; fibers; in silico simulations; inhalation therapy; respiratory tract.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic of the lung domains and dry powder inhaler (DPI) flow profile. (a) The in silico upper airways model consists of a mouth and throat, trachea, and 7 generations of the conducting airways, following [25]. (b) The bronchial tree model consists of 9 symmetrical generations of the bronchial airways, following [23]. (c) Profile of the DPI inhalation maneuver (i.e., flow rate) through the mouth as a function of time. Particle injection (marked in red) is confined to a short bolus, spanning 0.45 to 0.6 s [25].
Figure 2
Figure 2
Deposition maps for fibers with selected aspect ratios (AR; rows) and equivalent diameters (columns) at the end of the DPI maneuver (t = 3 s) in the upper airway domain. The particle deposition is color coded according to the number of neighbors within a 10 mm radius. It is clear that fibers of equivalnt diameter (dp) > 2 mm deposit less and disperse more compared to spheres. We note that 7 µm particles are strongly influenced by impaction, causing them to be deposited in the characteristic “hot spots” of the domain, although elongation (i.e., the AR) qualitatively increases dispersion outcomes.
Figure 3
Figure 3
Deposition maps for fibers with different aspect ratios (rows) and equivalent diameters (columns) at the end of the DPI maneuver (t = 3 s) in the nine-generation bronchial tree domain. Particle deposition is color coded (1–500) according to the number of neighbors within a 5 mm radius. It is clear that particles of dp > 2 µm fibers deposit less and disperse more compared to spheres. We note that as dp increases, particles are strongly influenced by impaction and sedimentation at the carinas, causing them to be deposited, although they are more dispersed as the AR increases.
Figure 4
Figure 4
Deposition efficiencies (DE) in upper airways model (a) and the bronchial bifurcating tree (b) as a function of dp and AR at the end of the DPI maneuver (t = 3 s). (a) As dp increases, particles deposit more and a significant effect of AR only appears for particles larger than 4 µm; as AR increases, DE decreases. For 20 µm particles, DE ~ 1 without observable differences between spheres and fibers. (b) DE in the bronchial tree is calculated by reducing the particles that already deposit in upper airways; therefore, an optimum is achieved for deposition in the bronchi. While small particles (dp < 3 µm) are screened through the domain due to convection, large particles (dp =10–20 µm) deposit in the upper airways due to inertial impaction and gravitational sedimentation. The optimum for particles deposition in the bronchi changes with AR, such that 5 µm spheres reach DE ~ 0.26 and 7 µm fibers of AR = 30 reach DE ~ 0.3.

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