Multiscale in silico lung modeling strategies for aerosol inhalation therapy and drug delivery

Koullapis, Pantelis; Ollson, Bo; Kassinos, Stavros C.; Sznitman, Josué

doi:10.1016/j.cobme.2019.11.003

Cited by 27 publications

(17 citation statements)

References 47 publications

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“…We discuss ongoing efforts in bridging the gap between in vivo and in vitro interfaces and identify some of the bioengineering challenges that lie ahead in delivering new generations of in vitro pulmonary platforms. As the breadth of the respiratory organ both in scale and complexity imposes an essentially "compartmental" approach [8,35] to emulate some but not all of its vast biological (e.g. cellular and immunological makeup) and physiological (e.g.…”

Section: Introductionmentioning

confidence: 99%

Advanced human-relevant in vitro pulmonary platforms for respiratory therapeutics

Artzy‐Schnirman

Raviv

Flikshtain

et al. 2021

Advanced Drug Delivery Reviews

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Over the past years, advanced in vitro pulmonary platforms have witnessed exciting developments that are pushing beyond traditional preclinical cell culture methods. Here, we discuss ongoing efforts in bridging the gap between in vivo and in vitro interfaces and identify some of the bioengineering challenges that lie ahead in delivering new generations of human-relevant in vitro pulmonary platforms. Notably, in vitro strategies using foremost lung-on-chips and biocompatible "soft" membranes have focused on platforms that emphasize phenotypical endpoints recapitulating key physiological and cellular functions. We review some of the most recent in vitro studies underlining seminal therapeutic screens and translational applications and open our discussion to promising avenues of pulmonary therapeutic exploration focusing on liposomes. Undeniably, there still remains a recognized trade-off between the physiological and biological complexity of these novel in vitro lung models and their ability to deliver assays with throughput capabilities. The upcoming years are thus anticipated to see further developments in broadening the applicability of such in vitro systems and accelerating therapeutic exploration for drug discovery and translational medicine in treating respiratory disorders.

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Section: Introductionmentioning

confidence: 99%

Advanced human-relevant in vitro pulmonary platforms for respiratory therapeutics

Artzy‐Schnirman

Raviv

Flikshtain

et al. 2021

Advanced Drug Delivery Reviews

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“…Only modelling the small number of airway bifurcation levels visible in the CT scan limits the model to only providing deposition information about the upper and central airways. To understand drug delivery in the smaller more distal airways the particles ‘exiting’ from our model’s outlets could be coupled to analytical 1D models (Koullapis et al, 2019). These models predict deposition based on particle size, estimated airway length and diameter, and flow rate.…”

Section: Discussionmentioning

confidence: 99%

“…To understand drug delivery in the smaller more distal airways the particles 'exiting' from our model's outlets could be coupled to analytical 1D models (Kuprat et al, 2020;Koullapis et al, 2019). These models predict deposition based on particle size, estimated airway length and diameter, and flow rate.…”

Section: Discussionmentioning

confidence: 99%

Image-based modelling of inhaler deposition during respiratory exacerbation

Williams

Kolehmainen

Cunningham

et al. 2020

Preprint

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For many of the one billion sufferers of respiratory diseases worldwide, managing their disease with inhalers improves their ability to breathe. Poor disease management and rising pollution can trigger exacerbations which require urgent relief. Higher drug deposition in the throat instead of the lungs limits the impact on patient symptoms. To optimise delivery to the lung, patient-specific computational studies of aerosol inhalation can be used. However in many studies, inhalation modelling does not represent an exacerbation, where the patient's breath is much faster and shorter. Here we compare differences in deposition of inhaler particles in the airways of a healthy male, female lung cancer and child cystic fibrosis patient. We aimed to evaluate deposition differences during an exacerbation with image-based healthy and diseased patient models. We found that during an exacerbation, particles progressing to the lower airways were distributed similarly to those inhaled during healthy breathing, but fewer in quantity. Throat deposits were halved in the healthy patient compared to the diseased patients under extreme inhalation, due to changes in the detailed shape of the throat. Our results identify that the modelled upper airway must be patient-specific, and an exacerbating profile tested for optimal measurement of reliever inhaler deposition.

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“…As recently highlighted [23,24], spatially and temporally resolving airflow and aerosol transport dynamics across a complete lung model with vast multiscale properties spanning over 20 airway bifurcations of the pulmonary tree requires high computational resources that are still typically beyond reach. In turn, our strategy revolves around in silico numerical simulations of ellipsoid-shaped fibers of varying equivalent diameters (d p ) and aspect ratios (AR) in an upper airways model and a bronchial tree, adopting a multiscale approach in the footsteps of Koullapis et al [23].…”

Section: Airway Geometry and Inhalation Conditionsmentioning

confidence: 99%

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

et al. 2020

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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.

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Multiscale in silico lung modeling strategies for aerosol inhalation therapy and drug delivery

Cited by 27 publications

References 47 publications

Advanced human-relevant in vitro pulmonary platforms for respiratory therapeutics

Advanced human-relevant in vitro pulmonary platforms for respiratory therapeutics

Image-based modelling of inhaler deposition during respiratory exacerbation

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

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