Revisiting Airflow and Aerosol Transport Phenomena in the Deep Lungs with Microfluidics

Abstract

The dynamics of respiratory airflows and the associated transport mechanisms of inhaled aerosols characteristic of the deep regions of the lungs are of broad interest in assessing both respiratory health risks and inhalation therapy outcomes. In the present review, we present a comprehensive discussion of our current understanding of airflow and aerosol transport phenomena that take place within the unique and complex anatomical environment of the deep lungs, characterized by submillimeter 3D alveolated airspaces and nominally slow resident airflows, known as low-Reynolds-number flows. We exemplify the advances brought forward by experimental efforts, in conjunction with numerical simulations, to revisit past mechanistic theories of respiratory airflow and particle transport in the distal acinar regions. Most significantly, we highlight how microfluidic-based platforms spanning the past decade have accelerated opportunities to deliver anatomically inspired in vitro solutions that capture with sufficient realism and accuracy the leading mechanisms governing both respiratory airflow and aerosol transport at true scale. Despite ongoing challenges and limitations with microfabrication techniques, the efforts witnessed in recent years have provided previously unattainable in vitro quantifications on the local transport properties in the deep pulmonary acinar airways. These may ultimately provide new opportunities to explore improved strategies of inhaled drug delivery to the deep acinar regions by investigating further the mechanistic interactions between airborne particulate carriers and respiratory airflows at the pulmonary microscales.

Human Multi-Compartment Airways-on-Chip Platform for Emulating Respiratory Airborne Transmission: From Nose to Pulmonary Acini

“…Note that while the nasal and bronchial apical compartments are connected directly (i.e., flow rate is conserved), air flow continuing from the bronchial to the acinar apical compartment is split by a flow diverter, which releases pressure to the ambient environment thereby reducing the flowrate into the acinar chip (see details below). Following the Y-joint diverter, flow measurements reflect a reduced input flowrate of approximately 0.2 ml/min (i.e., 0.003 ml/s) corresponding to an inlet Reynolds number of ∼0.3 at the first generation of the acinar tree and well in line with characteristic acinar flows ( Sznitman, 2013 , 2021 ). This implies that only 3% of the flow continues past the Y-joint to the acinar compartment, due to the pressure gradient between the open end (ambient, low pressure) and high pressure from an increasingly smaller passage in the acinar chip.…”

“…To this end, we select the nasal passages, bronchial airways and acinar regions as three compartments representative of the extra-thoracic, conductive and respiratory regions, respectively (see Figure 1A ). Here, specifically, the apical partition of each chip compartment is designed to recapitulate relevant geometrical features of each lung region, and most critically where anatomical structures are known to influence airflow mechanics ( Sznitman, 2021 ). Below we detail design considerations relevant to each compartment.…”

“…The general acinar tree design features a multi-generation asymmetrically bifurcating network with alveolated airways that span several generations. Briefly, the device holds one inlet airway splitting into six branching generations of 170 μm width and 100 μm height channels, with spherical-like cavities mimicking alveoli of 155 μm diameter; the dimensions of the acinar airway chip are selected to match realistic anatomical dimensions pertinent to the distal respiratory regions of the lungs ( Artzy-Schnirman et al, 2019b ; Sznitman, 2021 ). Note that the microfluidic chip provides equal airflow to each terminal end of the model by adjusting the length of a channel connecting the unified outlet of the device and the last generation of the acinar tree ( Figure 3C ); this design guarantees equal airflow at each terminal end of the acinar model (for further details, see Artzy-Schnirman et al, 2019b ).…”

“…Concurrently, small, recirculating flows in the alveolar-like cavities are present along the alveolated airway channels. Further details on the flow characteristics, including aerosol deposition, in microfluidic acinar airways are available elsewhere using the same geometry ( Sznitman, 2021 ).…”

An In Vitro Microfluidic Alveolus Model to Study Lung Biomechanics

“…Model systems incorporate such dynamic mechanical movements associated with breathing using deformable membranes subjected to dynamic pressure (Guenat and Berthiaume, 2018). While most in vitro studies and microphysiological systems incorporating dynamic stretch have been limited to generating in-plane strain or uniaxial strain in the 5-12% range reported in vivo (Birukov et al, 2003;Guenat and Berthiaume, 2018;Nossa et al, 2021;Sznitman, 2021), recent studies have delved into incorporating out-of-plane stretching to mimic the 3D movements of the alveoli during respiration (Stucki et al, 2018;Doryab et al, 2021a;Huang et al, 2021;Zamprogno et al, 2021). These advances offer unique in vitro tools to study the micromechanical changes such as the strain heterogeneity that develops as a result of the out-of-plane stretch and its subsequent role in lung physiology and pathology.…”