Particle transport phenomena in the deep alveolated airways of the lungs (i.e. pulmonary acinus) govern deposition outcomes following inhalation of hazardous or pharmaceutical aerosols. Yet, there is still a dearth of experimental tools for resolving acinar particle dynamics and validating numerical simulations. Here, we present a true-scale experimental model of acinar structures consisting of bifurcating alveolated ducts that capture breathing-like wall motion and ensuing respiratory acinar flows. We study experimentally captured trajectories of inhaled polydispersed smoke particles (0.2 to 1 μm in diameter), demonstrating how intrinsic particle motion, i.e. gravity and diffusion, is crucial in determining dispersion and deposition of aerosols through a streamline crossing mechanism, a phenomenon paramount during flow reversal and locally within alveolar cavities. A simple conceptual framework is constructed for predicting the fate of inhaled particles near an alveolus by identifying capture and escape zones and considering how streamline crossing may shift particles between them. In addition, we examine the effect of particle size on detailed deposition patterns of monodispersed microspheres between 0.1–2 μm. Our experiments underline local modifications in the deposition patterns due to gravity for particles ≥0.5 μm compared to smaller particles, and show good agreement with corresponding numerical simulations.
The entire luminal surface of the lungs is populated with a complex yet confluent, uninterrupted airway epithelium in conjunction with an extracellular liquid lining layer that creates the air-liquid interface (ALI), a critical feature of healthy lungs. Motivated by lung disease modelling, cytotoxicity studies, and drug delivery assessments amongst other, in vitro setups have been traditionally conducted using macroscopic cultures of isolated airway cells under submerged conditions or instead using transwell inserts with permeable membranes to model the ALI architecture. Yet, such strategies continue to fall short of delivering a sufficiently realistic physiological in vitro airway environment that cohesively integrates at true-scale three essential pillars: morphological constraints (i.e., airway anatomy), physiological conditions (e.g., respiratory airflows), and biological functionality (e.g., cellular makeup). With the advent of microfluidic lung-on-chips, there have been tremendous efforts towards designing biomimetic airway models of the epithelial barrier, including the ALI, and leveraging such in vitro scaffolds as a gateway for pulmonary disease modelling and drug screening assays. Here, we review in vitro platforms mimicking the pulmonary environment and identify ongoing challenges in reconstituting accurate biological airway barriers that still widely prevent microfluidic systems from delivering mainstream assays for the end-user, as compared to macroscale in vitro cell cultures. We further discuss existing hurdles in scaling up current lung-on-chip designs, from single airway models to more physiologically realistic airway environments that are anticipated to deliver increasingly meaningful whole-organ functions, with an outlook on translational and precision medicine.
The dispersion of inhaled microparticles in the pulmonary acinus of the lungs is often attributed to the complex interplay between convective mixing, due to irreversible flows, and intrinsic particle motion (i.e. gravity and diffusion). However, the role of each mechanism, the exact nature of such interplay between them and their relative importance still remain unclear. To gain insight into these dispersive mechanisms, we track liquid-suspended microparticles and extract their effective diffusivities inside an anatomically-inspired microfluidic acinar model. Such results are then compared to experiments and numerical simulations in a straight channel. While alveoli of the proximal acinar generations exhibit convective mixing characteristics that lead to irreversible particle trajectories, this local effect is over-shadowed by a more dominant dispersion mechanism across the ductal branching network that arises from small but significant streamline crossing due to intrinsic diffusional motion in the presence of high velocity gradients. We anticipate that for true airborne particles, which exhibit much higher intrinsic motion, streamline crossing would be even more significant.
Quantifying respiratory flow characteristics in the pulmonary acinar depths and how they influence inhaled aerosol transport is critical towards optimizing drug inhalation techniques as well as predicting deposition patterns of potentially toxic airborne particles in the pulmonary alveoli. Here, soft-lithography techniques are used to fabricate complex acinar-like airway structures at the truthful anatomical length-scales that reproduce physiological acinar flow phenomena in an optically accessible system. The microfluidic device features 5 generations of bifurcating alveolated ducts with periodically expanding and contracting walls. Wall actuation is achieved by altering the pressure inside water-filled chambers surrounding the thin PDMS acinar channel walls both from the sides and the top of the device. In contrast to common multilayer microfluidic devices, where the stacking of several PDMS molds is required, a simple method is presented to fabricate the top chamber by embedding the barrel section of a syringe into the PDMS mold. This novel microfluidic setup delivers physiological breathing motions which in turn give rise to characteristic acinar air-flows. In the current study, micro particle image velocimetry (µPIV) with liquid suspended particles was used to quantify such air flows based on hydrodynamic similarity matching. The good agreement between µPIV results and expected acinar flow phenomena suggest that the microfluidic platform may serve in the near future as an attractive in vitro tool to investigate directly airborne representative particle transport and deposition in the acinar regions of the lungs.
Nanoscale organization of surface ligands often has a critical effect on cell-surface interactions. We have developed an experimental system that allows a high degree of control over the 2-D spatial distribution of ligands. As a proof of concept, we used the developed system to study how T-cell activation is independently affected by antigen density and antigen amount per cell. Arrays of submicrometer gold islands at varying surface coverage were defined on silicon by electron beam lithography (EBL). The gold islands were functionalized with alkanethiol self-assembled monolayers (SAMs) containing a small antigen, 2,4,6-trinotrophenyl (TNP), at various densities. Genetically engineered T-cell hybridomas expressing TNP-specific chimeric T-cell antigen receptor (CAR) were cultured on the SAMs, and their activation was assessed by IL-2 secretion and CD69 expression. It was found that, at constant antigen density, activation increased monotonically with the amount of antigen, while at constant antigen amount activation was maximal at an intermediate antigen density, whose value was independent of the amount of antigen.
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