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

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.

SUBMITTER: Shachar-Berman L

PROVIDER: S-EPMC7150950 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe increased production of nanomaterials has caused a corresponding increase in concern about human exposures in consumer and occupational settings. Studies in rodents have evaluated dose-response relationships following respiratory tract (RT) delivery of nanoparticles (NPs) in order to identify potential hazards. However, these studies often use bolus methods that deliver NPs at high dose rates that do not reflect real world exposures and do not measure the actual deposited dose of NPs. We hypothesize that the delivered dose rate is a key determinant of the inflammatory response in the RT when the deposited dose is constant.MethodsF-344 rats were exposed to the same deposited doses of titanium dioxide (TiO?) NPs by single or repeated high dose rate intratracheal instillation or low dose rate whole body aerosol inhalation. Controls were exposed to saline or filtered air. Bronchoalveolar lavage fluid (BALF) neutrophils, biochemical parameters and inflammatory mediator release were quantified 4, 8, and 24 hr and 7 days after exposure.ResultsAlthough the initial lung burdens of TiO? were the same between the two methods, instillation resulted in greater short term retention than inhalation. There was a statistically significant increase in BALF neutrophils at 4, 8 and 24 hr after the single high dose TiO? instillation compared to saline controls and to TiO? inhalation, whereas TiO? inhalation resulted in a modest, yet significant, increase in BALF neutrophils 24 hr after exposure. The acute inflammatory response following instillation was driven primarily by monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, mainly within the lung. Increases in heme oxygenase-1 in the lung were also higher following instillation than inhalation. TiO? inhalation resulted in few time dependent changes in the inflammatory mediator release. The single low dose and repeated exposure scenarios had similar BALF cellular and mediator response trends, although the responses for single exposures were more robust.ConclusionsHigh dose rate NP delivery elicits significantly greater inflammation compared to low dose rate delivery. Although high dose rate methods can be used for quantitative ranking of NP hazards, these data caution against their use for quantitative risk assessment.

Project description:BACKGROUND:Although nanoparticles and their hazardous effects on human health are well elucidated meanwhile, inhalation and distribution of these materials in the human respiratory tract still represent partly enigmatic phenomena. Main objective of the present study was the detailed description of a mathematical method, with the help of which spatial distributions of nanoparticles deposited in the tracheobronchial tree may be visualized appropriately. METHODS:The technique is founded on a stochastic model of the bronchial network, within which inhaled particles follow individual, randomly selected trajectories. The lengths of these random paths depend on the airway-specific deposition probabilities calculated for the particles and the duration of the breath cycle. Positions of the deposited material were determined by computation of the exact lengths of individual particle trajectories and the orientation of single path segments within a Cartesian coordinate system, where the z-direction corresponds with the trachea. For a better quantification of the particle distribution and its eventual comparison with experimental data particle coordinates were fitted into a voxel grid [1 voxel = (0.467 cm)(3)]. Particle deposition is chiefly controlled by diffusive processes, whereas deposition mechanisms associated with inertia or gravity play a subordinate role. RESULTS:Deposition patterns were visualized for particles with sizes of 1, 10, and 100 nm. As clearly demonstrated by the results obtained from the modeling procedure, under normal breathing conditions 1-nm particles tend to deposit in the upper airways, whilst 10- and 100-nm particles are preferably accumulated in the airways of the central and peripheral lung. The particle dose deposited in the extrathoracic and thoracic airways within one breath cycle significantly declines with increasing particle size. CONCLUSIONS:Based on the predictions presented in this study possible consequences of nanoparticle inhalation to the health of subjects increasingly exposed to these airborne materials were discussed.

Project description:Accurate knowledge of the delivery of locally acting drug products, such as metered-dose inhaler (MDI) formulations, to large and small airways is essential to develop reliable in vitro/in vivo correlations (IVIVCs). However, challenges exist in modeling MDI delivery, due to the highly transient multiscale spray formation, the large variability in actuation-inhalation coordination, and the complex lung networks. The objective of this study was to develop/validate a computational MDI-releasing-delivery model and to evaluate the device actuation effects on the dose distribution with the newly developed model. An integrated MDI-mouth-lung (G9) geometry was developed. An albuterol MDI with the chlorofluorocarbon propellant was simulated with polydisperse aerosol size distribution measured by laser light scatter and aerosol discharge velocity derived from measurements taken while using a phase Doppler anemometry. The highly transient, multiscale airflow and droplet dynamics were simulated by using large eddy simulation (LES) and Lagrangian tracking with sufficiently fine computation mesh. A high-speed camera imaging of the MDI plume formation was conducted and compared with LES predictions. The aerosol discharge velocity at the MDI orifice was reversely determined to be 40 m/s based on the phase Doppler anemometry (PDA) measurements at two different locations from the mouthpiece. The LES-predicted instantaneous vortex structures and corresponding spray clouds resembled each other. There are three phases of the MDI plume evolution (discharging, dispersion, and dispensing), each with distinct features regardless of the actuation time. Good agreement was achieved between the predicted and measured doses in both the device, mouth-throat, and lung. Concerning the device-patient coordination, delayed MDI actuation increased drug deposition in the mouth and reduced drug delivery to the lung. Firing MDI before inhalation was found to increase drug loss in the device; however, it also reduced mouth-throat loss and increased lung doses in both the central and peripheral regions.

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

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