Background: While the nasopharynx is initially the dominant upper airway infection site for SARS-CoV-2, the physiologic mechanism launching the infection at the lower airway is still not well-understood. Based on the rapidity of infection progression to the lungs, it has been hypothesized that the nasopharynx may be acting as the primary seeding zone for subsequent contamination of the lower airway via aspiration of virus-laden boluses of nasopharyngeal fluids. Methodology: To examine the plausibility of the aspiration-driven mechanism, we have computationally tracked the inhalation process in three anatomic airway reconstructions and have quantified the nasopharyngeal liquid volume transmitted to the lower airspace during each aspiration. Results: Extending the numerical trends on aspiration volume to earlier records on aspiration frequencies indicates a total aspirated nasopharyngeal liquid volume of 0.3 – 0.76 ml/day. Subsequently, for mean sputum viral load, our modeling projects that the number of virions reaching the lower airway will range over 2.1×106 – 5.3×106 /day; for peak viral load, the corresponding number hovers between 7.1×108 – 1.8×109. Conclusions: The virion transmission findings fill in a key piece of the mechanistic puzzle on the systemic progression of SARS-CoV-2, and subjectively point to health conditions like dysphagia, with proclivity to increased aspiration, as some of the potential underlying risk factors for aggressive lung infections.

Drug delivery for viral respiratory infections, such as SARS-CoV-2, can be enhanced significantly by targeting the nasopharynx, which is the dominant initial infection site in the upper airway, for example by nasal sprays. However, under the standard recommended spray usage protocol ("Current Use", or CU), the nozzle enters the nose almost vertically, resulting in sub-optimal deposition of drug droplets at the nasopharynx. Using computational fluid dynamics simulations in two anatomic nasal geometries, along with experimental validation of the generic findings in a different third subject, we have identified a new "Improved Use" (or, IU) spray protocol. It entails pointing the spray bottle at a shallower angle (almost horizontally), aiming slightly toward the cheeks. We have simulated the performance of this protocol for conically injected spray droplet sizes of 1 - 24 microns, at two breathing rates: 15 and 30 L/min. The lower flowrate corresponds to resting breathing and follows a viscous-laminar model; the higher rate, standing in for moderate breathing conditions, is turbulent and is tracked via Large Eddy Simulation. The results show that (a) droplets sized between ~ 6 - 14 microns are most efficient at direct landing over the nasopharyngeal viral infection hot-spot; and (b) targeted drug delivery via IU outperforms CU by approximately 2 orders-of-magnitude, under the two tested inhalation conditions. Also quite importantly, the improved delivery strategy, facilitated by the IU protocol, is found to be robust to small perturbations in spray direction, underlining the practical utility of this simple change in nasal spray administration protocol.

Mammals have presumably evolved to adapt to a diverse range of ambient environmental conditions through the optimized heat and mass exchange. One of the crucial biological structures for survivability is the nose, which efficiently transports and thermally pre-conditions the external air before reaching the internal body. Nasal mucosa and cavity help warm and humidify the inhaled air quickly. Despite its crucial role, the morphological features of mammal noses and their effect in modulating the momentum of the inhaled air, heat transfer dynamics and particulate trapping remain poorly understood. Tortuosity of the nasal cavity in high-olfactory mammalian species, such as pigs and opossum, facilitates the formation of complex airflow patterns inside the nasal cavity, that leads to the screening of particulates from the inhaled air. We explored basic nasal features in anatomically realistic nasal pathways, including tortuosity, the radius of curvature, and gap thickness; they show strong power-law correlations with body weight. Complementary inspection of tortuosity with idealized conduits reveals that this quantity is central in particle capture efficiency. Mechanistic insights into such nuances can serve as a tipping point to transforming nature-based designs into practical applications. In-depth characterization of the fluid-particle interactions in nasal cavities is necessary to uncover nose mechanistic functionalities. It is instrumental in developing new devices and filters in a number of engineering processes.

The nasopharynx, at the back of the nose, constitutes the dominant initial viral infection trigger zone along the upper respiratory tract. However, as per the standard recommended usage protocol (“Current Use”, or CU) for intranasal sprays, the nozzle should enter the nose almost vertically, resulting in sub-optimal nasopharyngeal drug deposition. Through the Large Eddy Simulation technique, this study has replicated airflow under standard breathing conditions with 15 and 30 L/min inhalation rates, passing through medical scan-based anatomically accurate human airway cavities. The small-scale airflow fluctuations were resolved through use of a sub-grid scale Kinetic Energy Transport Model. Intranasally sprayed droplet trajectories for different spray axis placement and orientation conditions were subsequently tracked via Lagrangian-based inert discrete phase simulations against the ambient inhaled airflow field. Finally, this study verified the computational projections for the upper airway drug deposition trends against representative physical experiments on sprayed delivery performed in a 3D-printed anatomic replica. The model-based exercise has revealed a new “Improved Use” (or, IU) spray usage protocol for viral infections. It entails pointing the spray bottle at a shallower angle (with an almost horizontal placement at the nostril), aiming slightly toward the cheeks. From the conically injected spray droplet simulations, we have summarily derived the following inferences: (a) droplets sized between 7–17 μm are relatively more efficient at directly reaching the nasopharynx via inhaled transport; and (b) with realistic droplet size distributions, as found in current over-the-counter spray products, the targeted drug delivery through the IU protocol outperforms CU by a remarkable 2 orders-of-magnitude.

Dense fibrous extracellular constitution of solid tumors exerts high resistance to diffusive transport into it; additionally, the scarcity of blood and lymphatic flows hinders convection. The complexity of fluidic transport mechanisms in such tumor environments still presents open questions with translational end goals. For example, clinical diagnosis and targeted drug delivery platforms for such dense tumors can ideally benefit from a quantitative framework on plasma uptake into the tumor. In this study, we present a computational model for physical parameters that may influence blood percolation and penetration into simple biomimetic solid tumor geometry. The model implements three-phase viscous-laminar transient simulation to mimic the transport physics inside a tumor-adhering blood vessel and measures the constituent volume fractions of the three considered phases, viz. plasma, RBCs (red blood cells, also known as “erythrocytes”), and WBCs (white blood cells, also known as “leukocytes”) at three different flow times, while simultaneously recording the plasma pressure and velocity at the entry point to the tumor’s extracellular space. Subsequently, to quantify plasma perfusion within the tumor zone, we proposed a reduced-order two-dimensional transport model for the tumor entry zone and its extracellular space for three different fenestra diameters: 0.1, 0.3, and 0.5 µm; the simulations were two-phase viscous-laminar transient. The findings support the hypothesis that plasma percolation into the tumor is proportional to the leakiness modulated by the size of fenestra openings, and the rate of percolation decays with the diffusion distance.