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Targeting inhaled fibers to the pulmonary acinus: Opportunities for augmented delivery from in silico simulations.

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 (d_p) and aspect ratio (AR). Our findings underscore how acinar deposition characteristics are intimately linked to the geometrical combination of d_p and AR under oscillatory flow conditions. Surprisingly, the elongation of the traditionally recommended size range of spherical particles (i.e., 2-3 μm) 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 μm 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.

SUBMITTER: Shachar-Berman L

PROVIDER: S-EPMC7611813 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Computational Fluid Dynamics (CFD) have offered an attractive gateway to investigate in silico respiratory flows and aerosol transport in the depths of the lungs. Yet, not only do existing models lack sufficient anatomical realism in capturing the heterogeneity and morphometry of the acinar environment, numerical simulations have been widely restricted to domains capturing a mere few percent of a single acinus. Here, we present to the best of our knowledge the most detailed and comprehensive in silico simulations to date on the fate of aerosols in the acinar depths. Our heterogeneous acinar domains represent complete sub-acinar models (i.e. 1/8th of a full acinus) based on the recent algorithm of Koshiyama & Wada (2015), capturing statistics of human acinar morphometry (Ochs et al. 2004). Our simulations deliver high-resolution, 3D spatial-temporal data on aerosol transport and deposition, emphasizing how variances in acinar heterogeneity only play a minor role in determining general deposition outcomes. With such tools at hand, we revisit whole-lung deposition predictions (i.e. ICRP) based on past 1D lung models. While our findings under quiet breathing substantiate general deposition trends obtained with past predictions in the alveolar regions, we underscore how deposition fractions are anticipated to increase, in particular during deep inhalation. For such inhalation maneuver, our simulations support the notion of significantly augmented deposition for all aerosol sizes (0.005-5.0?m). Overall, our efforts not only help consolidate our mechanistic understanding of inhaled aerosol transport in the acinar depths but also continue to bridge the gap between "bottom-up" in silico models and regional deposition predictions from whole-lung models. Such quantifications provide what is deemed more accurate deposition predictions in morphometrically-faithful models and are particularly useful in assessing inhalation strategies for deep airway deposition (e.g. systemic delivery).

Project description:BackgroundPulmonary hypertension due to chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) is classified as group 3 pulmonary hypertension. Inhaled treprostinil, a prostaglandin I2 analogue also known as prostacyclin, has recently been approved as a first drug for patients with pulmonary hypertension secondary to ILD. However, due to a lack of evidence, no therapies are currently approved for those with COPD-associated pulmonary hypertension. Thus, this systematic review aims to summarise the current evidence to assess the impact of inhaled prostaglandin I2 analogue use on the pulmonary hemodynamics, exercise function, lung function, and gas exchange in patients with pulmonary hypertension due to COPD.MethodsWe systematically searched the electronic databases of Medline, Embase, Scopus and Cochrane from inception to 1 February 2023. Studies of adult patients with a confirmed diagnosis of COPD-associated pulmonary hypertension who received inhaled drugs targeting the prostacyclin pathway were included in the systematic review. Case reports, systematic reviews, conference abstracts with no full text, non-full-text articles, non-English manuscripts and book chapters were excluded from this systematic review. A risk-of-bias assessment was carried out for the studies included in this review, using two different Cochrane risk-of-bias tools for randomised and non-randomised clinical trials.ResultsA total of four studies met our inclusion criteria and were included in this systematic review. The results of one prospective clinical trial showed an improvement in the pulmonary hemodynamics (e.g., cardiac index, cardiac output and mean pulmonary artery pressure) in response to inhaled prostacyclin use in patients with pulmonary hypertension secondary to COPD. However, the severity of dyspnoea, lung function, exercise capacity and gas exchange were not affected when inhaled prostacyclin was used for patients with COPD-related pulmonary hypertension.ConclusionThis systematic review demonstrated that although inhaled prostacyclin does not seem to improve COPD-related outcomes (e.g., lung function and exercise capacity), short-term use of inhaled prostacyclin has the potential to reduce mean pulmonary artery pressure and pulmonary vascular resistance without impairing ventilation-perfusion mismatch. Further studies with larger sample sizes are warranted.Systematic review registrationCRD42022372803, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=372803.

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Targeting inhaled fibers to the pulmonary acinus: Opportunities for augmented delivery from in silico simulations.

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