Alveolar duct expansion greatly enhances aerosol deposition: a three-dimensional computational fluid dynamics study

Obtaining in vivo data of particle transport in the human lung is often difficult, if not impossible. Computational fluid dynamics (CFD) can provide detailed information on aerosol transport in realistic airway geometries. This paper provides a review of the key CFD studies of aerosol transport in the acinar region of the human lung. It also describes the first ever three-dimensional model of a single fully alveolated duct with moving boundaries allowing for the cyclic expansion and contraction that occurs during breathing. Studies of intra-acinar aerosol transport performed in models with stationary walls (SWs) showed that flow patterns were influenced by the geometric characteristics of the alveolar aperture, the presence of the alveolar septa contributed to the penetration of the particles into the lung periphery and there were large inhomogeneities in deposition patterns within the acinar structure. Recent studies have now used acinar models with moving walls. In these cases, particles penetrate the alveolar cavities not only as a result of sedimentation and diffusion but also as a result of convective transport, resulting in a much higher deposition prediction than that in SW models. Thus, models that fail to incorporate alveolar wall motions probably underestimate aerosol deposition in the acinar region of the lung

Regional Ventilation Is the Main Determinant of Alveolar Deposition of Coarse Particles in the Supine Healthy Human Lung during Tidal Breathing

Background: To quantify the relationship between regional lung ventilation and coarse aerosol deposition in the supine healthy human lung, we used oxygen-enhanced magnetic resonance imaging and planar gamma scintigraphy in seven subjects. Methods: Regional ventilation was measured in the supine posture in a 15 mm sagittal slice of the right lung. Deposition was measured by using planar gamma scintigraphy (coronal scans, 40 cm FOV) immediately postdeposition, 1 hour 30 minutes and 22 hours after deposition of 99mTc-labeled particles (4.9 μm MMAD, GSD 2.5), inhaled in the supine posture (flow 0.5 L/s, 15 breaths/min). The distribution of retained particles at different times was used to infer deposition in different airway regions, with 22 hours representing alveolar deposition. The fraction of total slice ventilation per quartile of lung height from the lung apex to the dome of the diaphragm at functional residual capacity was computed, and co-registered with deposition data - apices aligned - using a transmission scan as reference. The ratio of fractional alveolar deposition to fractional ventilation of each quartile (r) was used to evaluate ventilation and deposition matching (r > 1, regional aerosol deposition fraction larger than regional ventilation fraction). Results: r was not significantly different from 1 for all regions (1.04 ± 0.25, 1.08 ± 0.22, 1.03 ± 0.17, 0.92 ± 0.13, apex to diaphragm, p > 0.40) at the alveolar level (r22h). For retention times r0h and r1h30, only the diaphragmatic region at r1h30 differed significantly from 1. Conclusions: These results support the hypothesis that alveolar deposition is directly proportional to ventilation for ∼5 μm particles that are inhaled in the supine posture and are consistent with previous simulation predictions that show that convective flow is the main determinant of aerosol transport to the lung periphery

Airflow and Particle Deposition Simulations in Health and Emphysema: From In Vivo to In Silico Animal Experiments

International audienceImage-based in-silico modeling tools provide detailed velocity and particle deposition data. However, care must be taken when prescribing boundary conditions to model lung physiology in health or disease, such as in emphysema. In this study, the respiratory resistance and compliance were obtained by solving an inverse problem; a 0D global model based on healthy and emphysematous rat experimental data. Multi-scale CFD simulations were performed by solving the 3D Navier Stokes equations in an MRI-derived rat geometry coupled to a 0D model. Particles with 0.95 um diameter were tracked and their distribution in the lung was assessed. Seven 3D-0D simulations were performed: healthy, homogeneous, and five heterogeneous emphysema cases. Compliance (C) was significantly higher (p = 0.04) in the emphysematous rats (C = 0.37 +/- 0.14 cm^3 / cmH_2O) compared to the healthy rats (C = 0.25 +/- 0 0.04 cm^3 / cmH_2O), while the resistance remained unchanged (p = 0.83). There were increases in airflow, particle deposition in the 3D model, and particle delivery to the diseased regions for the heterogeneous cases compared to the homogeneous cases. The results highlight the importance of multi-scale numerical simulations to study airflow and particle distribution in healthy and diseased lungs. The effect of particle size and gravity were studied. Once available, these in-silico predictions may be compared to experimental deposition data

Evaluation of Aerosol Delivery of Nanosuspension for Pre-clinical Pulmonary Drug Delivery

Asthma and chronic obstructive pulmonary disease (COPD) are pulmonary diseases that are characterized by inflammatory cell infiltration, cytokine production, and airway hyper-reactivity. Most of the effector cells responsible for these pathologies reside in the lungs. One of the most direct ways to deliver drugs to the target cells is via the trachea. In a pre-clinical setting, this can be achieved via intratracheal (IT), intranasal (IN), or aerosol delivery in the desired animal model. In this study, we pioneered the aerosol delivery of a nanosuspension formulation in a rodent model. The efficiency of different dosing techniques and formulations to target the lungs were compared, and fluticasone was used as the model compound. For the aerosol particle size determination, a ten-stage cascade impactor was used. The mass median aerodynamic diameter (MMAD) was calculated based on the percent cumulative accumulation at each stage. Formulations with different particle size of fluticasone were made for evaluation. The compatibility of regular fluticasone suspension and nanosuspension for aerosol delivery was also investigated. The in vivo studies were conducted on mice with optimized setting. It was found that the aerosol delivery of fluticasone with nanosuspension was as efficient as intranasal (IN) dosing, and was able to achieve dose dependent lung deposition

Ventilation-perfusion inequality in the human lung is not increased following no-decompression-stop hyperbaric exposure

Venous gas bubbles occur in recreational SCUBA divers in the absence of decompression sickness, forming venous gas emboli (VGE) which are trapped within pulmonary circulation and cleared by the lung without overt pathology. We hypothesized that asymptomatic VGE would transiently increase ventilation-perfusion mismatch due to their occlusive effects within the pulmonary circulation. Two sets of healthy volunteers (n = 11, n = 12) were recruited to test this hypothesis with a single recreational ocean dive or a baro-equivalent dry hyperbaric dive. Pulmonary studies (intrabreath VA/Q (iV/Q), alveolar dead space, and FVC) were conducted at baseline and repeat 1- and 24-h after the exposure. Contrary to our hypothesis VA/Q mismatch was decreased 1-h post-SCUBA dive (iV/Q slope 0.023 ± 0.008 ml−1 at baseline vs. 0.010 ± 0.005 NS), and was significantly reduced 24-h post-SCUBA dive (0.000 ± 0.005, p < 0.05), with improved VA/Q homogeneity inversely correlated to dive severity. No changes in VA/Q mismatch were observed after the chamber dive. Alveolar dead space decreased 24-h post-SCUBA dive (78 ± 10 ml at baseline vs. 56 ± 5, p < 0.05), but not 1-h post dive. FVC rose 1-h post-SCUBA dive (5.01 ± 0.18 l vs. 5.21 ± 0.26, p < 0.05), remained elevated 24-h post SCUBA dive (5.06 ± 0.2, p < 0.05), but was decreased 1-hr after the chamber dive (4.96 ± 0.31 L to 4.87 ± 0.32, p < 0.05). The degree of VA/Q mismatch in the lung was decreased following recreational ocean dives, and was unchanged following an equivalent air chamber dive, arguing against an impact of VGE on the pulmonary circulation