publications

2023

1. In vitro–in silico correlation of three-dimensional turbulent flows in an idealized mouth-throat model

   Nof, Eliram, Bhardwaj, Saurabh, Koullapis, Pantelis, Bessler, Ron, Kassinos, Stavros, and Sznitman, Josué

   PLOS Computational Biology Mar 2023

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   There exists an ongoing need to improve the validity and accuracy of computational fluid dynamics (CFD) simulations of turbulent airflows in the extra-thoracic and upper airways. Yet, a knowledge gap remains in providing experimentally-resolved 3D flow benchmarks with sufficient data density and completeness for useful comparison with widely-employed numerical schemes. Motivated by such shortcomings, the present work details to the best of our knowledge the first attempt to deliver in vitro–in silico correlations of 3D respiratory airflows in a generalized mouth-throat model and thereby assess the performance of Large Eddy Simulations (LES) and Reynolds-Averaged Numerical Simulations (RANS). Numerical predictions are compared against 3D volumetric flow measurements using Tomographic Particle Image Velocimetry (TPIV) at three steady inhalation flowrates varying from shallow to deep inhalation conditions. We find that a RANS k-ω SST model adequately predicts velocity flow patterns for Reynolds numbers spanning 1’500 to 7’000, supporting results in close proximity to a more computationally-expensive LES model. Yet, RANS significantly underestimates turbulent kinetic energy (TKE), thus underlining the advantages of LES as a higher-order turbulence modeling scheme. In an effort to bridge future endevours across respiratory research disciplines, we provide end users with the present in vitro–in silico correlation data for improved predictive CFD models towards inhalation therapy and therapeutic or toxic dosimetry endpoints.

2022

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

   Nof*, E., Zidan*, H., Artzy-Schnirman, A., Mouhadeb, O., Beckerman, M., Bhardwaj, S., Kirma-Elias, S., Gur, D., Beth-Din, A., Levenberg, S., Korin, N., Ordentlich, A., and Sznitman, J.

   Frontiers in Physiology Mar 2022

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   The past decade has witnessed tremendous endeavors to deliver novel preclinical in vitro lung models for pulmonary research endpoints, including foremost with the advent of organ- and lung-on-chips. With growing interest in aerosol transmission and infection of respiratory viruses within a host, most notably the SARS-CoV-2 virus amidst the global COVID-19 pandemic, the importance of crosstalk between the different lung regions (i.e., extra-thoracic, conductive and respiratory), with distinct cellular makeups and physiology, are acknowledged to play an important role in the progression of the disease from the initial onset of infection. In the present Methods article, we designed and fabricated to the best of our knowledge the first multi-compartment human airway-on-chip platform to serve as a preclinical in vitro benchmark underlining regional lung crosstalk for viral infection pathways. Combining microfabrication and 3D printing techniques, our platform mimics key elements of the respiratory system spanning (i) nasal passages that serve as the alleged origin of infections, (ii) the mid-bronchial airway region and (iii) the deep acinar region, distinct with alveolated airways. Crosstalk between the three components was exemplified in various assays. First, viral-load (including SARS-CoV-2) injected into the apical partition of the nasal compartment was detected in distal bronchial and acinar components upon applying physiological airflow across the connected compartment models. Secondly, nebulized viral-like dsRNA, poly I:C aerosols were administered to the nasal apical compartment, transmitted to downstream compartments via respiratory airflows and leading to an elevation in inflammatory cytokine levels secreted by distinct epithelial cells in each respective compartment. Overall, our assays establish an in vitro methodology that supports the hypothesis for viral-laden airflow mediated transmission through the respiratory system cellular landscape. With a keen eye for broader end user applications, we share detailed methodologies for fabricating, assembling, calibrating, and using our multi-compartment platform, including open-source fabrication files. Our platform serves as an early proof-of-concept that can be readily designed and adapted to specific preclinical pulmonary research endpoints.

2021

1. Ventilation-induced epithelial injury drives biological onset of lung trauma in vitro and is mitigated with anti-inflammatory therapeutics

   Nof, E., Artzy-Schnirman, A., Bhardwaj, S., Sabatan, H., Waisman, D., Hochwald, O., Gruber, M., Borenstein-Levin, L., and Sznitman, J.

   Bioengineering & Translational Medicine Mar 2021

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   Mortality rates among patients suffering from acute respiratory failure remain perplexingly high despite the maintenance of blood oxygen homeostasis during ventilatory support. The biotrauma hypothesis advocates that mechanical forces from invasive ventilation trigger immunological mediators that spread systemically. Yet, how these forces elicit an immune response remains unclear. Here, a biomimetic in vitro three-dimensional (3D) upper airways model allows to recapitulate lung injury and immune responses induced during invasive mechanical ventilation in neonates. Under such ventilatory support, flow-induced stresses injure the bronchial epithelium of the intubated airways model and directly modulate epithelial cell inflammatory cytokine secretion associated with pulmonary injury. Fluorescence microscopy and biochemical analyses reveal site-specific susceptibility to epithelial erosion in airways from jet-flow impaction and are linked to increases in cell apoptosis and modulated secretions of cytokines IL-6, -8, and -10. In an effort to mitigate the onset of biotrauma, prophylactic pharmacological treatment with Montelukast, a leukotriene receptor antagonist, reduces apoptosis and pro-inflammatory signaling during invasive ventilation of the in vitro model. This 3D airway platform points to a previously overlooked origin of lung injury and showcases translational opportunities in preclinical pulmonary research toward protective therapies and improved protocols for patient care.

2020

1. In silico optimization of targeted aerosol delivery in upper airways via Inhaled Volume Tracking

   Heller-Algazi, M.,  Nof, E., Das, P., Bhardwah, S., Kassinos, S. C., and Sznitman, J.

   Clinical Biomechanics Mar 2020

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   Despite the widespread use of aerosol inhalation as a drug delivery method, targeted delivery to the upper airways remains an ongoing challenge in the quest for improved clinical response in respiratory disease.Here, we examine in silico flow and particle dynamics when using an oral Inhaled Volume Tracking manoeuvre. A short pulsed aerosol bolus is injected during slow inhalation flow rates followed by clean air, and a breath-hold is initiated once it reaches the desired depth. We explore the fate of a broad particle size range (1-40 μm) for both upright and supine positions. Our findings illustrate that despite attempts to mitigate dispersion using slower flow rates, the laryngeal jet disperses the aerosol bolus and thus remains a hurdle for efficient targeted delivery. Nevertheless, we show a decrease in extra-thoracic deposition; large aerosols in the range of 10-30 μm potentially outperform existing inhalation methods, showing deposition fractions of up to 80% in an upright orientation. The improved deposition during Inhaled Volume Tracking shows promise for clinical applications and could be leveraged to deliver larger payloads to the upper airways.

2. Ventilation-induced jet suggests biotrauma in reconstructed airways of the intubated neonate

   Nof, E., Heller-Algazi, M., Coletti, F., Waisman, D., and Sznitman, J.

   Journal of the Royal Society Interface Mar 2020

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   We investigate respiratory flow phenomena in a reconstructed upper airway model of an intubated neonate undergoing invasive mechanical ventilation, spanning conventional to high-frequency ventilation (HFV) modes. Using high-speed tomographic particle image velocimetry, we resolve transient, three-dimensional flow fields and observe a persistent jet flow exiting the endotracheal tube whose strength is directly modulated according to the ventilation protocol. We identify this synthetic jet as the dominating signature of convective flow under intubated ventilation. Concurrently, our in silico wall shear stress analysis reveals a hitherto overlooked source of ventilator-induced lung injury as a result of jet impingement on the tracheal carina, suggesting damage to the bronchial epithelium; this type of injury is known as biotrauma. We find HFV advantageous in mitigating the intensity of such impingement, which may contribute to its role as a lung protective method. Our findings may encourage the adoption of less invasive ventilation procedures currently used in neonatal intensive care units.

2019

1. Revisiting high-frequency oscillatory ventilation in vitro and in silico in neonatal conductive airways

   Bauer, K.,  Nof, E., and Sznitman, J.

   Clinical Biomechanics Mar 2019

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   High frequency oscillatory ventilation is often used for lung support in premature neonates suffering from respiratory distress syndrome. Despite its broad use in neonatal intensive care units, there are to date no accepted protocols for the choice of appropriate ventilation parameter settings. In this context, the underlying mass transport mechanisms are still not fully understood. We revisit the question of flow phenomena under conventional mechanical ventilation and high frequency oscillatory ventilation in an anatomically-inspired model of neonatal conductive airways spanning the first few airway generations. We first perform at true scale in vitro particle image velocimetry measurements of respiratory flow patterns. Next, we explore in silico convective mass transport in computational fluid dynamics simulations by implementing Lagrangian tracking of tracer boli, where the ventilatory flow rate is fixed. Particle image velocimetry measurements at eight representative phase angles of a breathing cycle reveal similar flow patterns at peak velocity and during deceleration phases for conventional mechanical ventilation and high frequency oscillatory ventilation. Characteristic differences occur during the acceleration and flow reversal phases. Net displacements of the tracer particles rapidly reach asymptotic behaviour over cumulative breathing cycles and suggest a linear relation between tidal volume and convective mass transport. The linear relation observed suggests that differences in flow characteristics between conventional mechanical ventilation and high frequency oscillatory ventilation conditions do not substantially influence convective mass transport mechanisms. Lower tidal volumes thus cannot be compensated straightforwardly by selecting higher frequencies to maintain similar ventilation efficiencies.

2018

1. Targeting inhaled aerosol delivery to upper airways in children: Insight from computational fluid dynamics (CFD)

   Das, P.,  Nof, E., Amirav, I., Kassinos, S. C., and Sznitman, J.

   PloS one Mar 2018

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   Despite the prevalence of inhalation therapy in the treatment of pediatric respiratory disorders, most prominently asthma, the fraction of inhaled drugs reaching the lungs for maximal efficacy remains adversely low. By and large drug delivery devices and their inhalation guidelines are typically derived from adult studies with child dosages adapted according to body weight. While it has long been recognized that physiological (e.g. airway sizes, breathing maneuvers) and physical transport (e.g. aerosol dynamics) characteristics are critical in governing deposition outcomes, such knowledge has yet to be extensively adapted to younger populations. Motivated by such shortcomings, the present work leverages in a first step in silico computational fluid dynamics (CFD) to explore opportunities for augmenting aerosol deposition in children based on respiratory physiological and physical transport determinants. Using an idealized, anatomically-faithful upper airway geometry, airflow and aerosol motion are simulated as a function of age, spanning a five year old to an adult. Breathing conditions mimic realistic age-specific inhalation maneuvers representative of Dry Powder Inhalers (DPI) and nebulizer inhalation. Our findings point to the existence of a single dimensionless curve governing deposition in the conductive airways via the dimensionless Stokes number (Stk). Most significantly, we uncover the existence of a distinct deposition peak irrespective of age. For the DPI simulations, this peak ( 80%) occurs at Stk ≈ 0.06 whereas for nebulizer simulations, the corresponding peak ( 45%) occurs in the range of Stk between 0.03-0.04. Such dimensionless findings hence translate to an optimal window of micron-sized aerosols that evolves with age and varies with inhalation device. The existence of such deposition optima advocates revisiting design guidelines for optimizing deposition outcomes in pediatric inhalation therapy.

2. Small-scale blast wave experiments by means of an exploding wire

   Sadot, O., Ram, O.,  Nof, E., Kochavi, E., and Ben-Dor, G.

   In Blast Effects Mar 2018

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   The effort invested in improving our understanding of the physics of high energy explosion events has tremendously increased in the past few decades. Moreover, the dramatic increase in computer capabilities over the last two decades made the numerical simulation approach the dominant tool for investigating blast wave related phenomena and their effects. However, both large- and small-scale field tests are still in use. In the following, we present an experimental tool capable of better resolving and studying the blast-structure interaction phenomenon. In addition, this experimental tool can assist in validating numerical simulations of these phenomena prior to applying them to simulate large-scale events. The experimental tool uses an exploding wire technique to generate small-scale cylindrical and spherical blast waves. This approach permits safe operation, high repeatability, and usage of advanced diagnostic systems that cannot be used in large-scale field experiments. The system was calibrated using an analytical model, an empirical model, and a numerical simulation. To ensure that spherical blast geometry was achieved, a set of free air blast experiments in which high-speed photography was used to monitor the blast wave structure was conducted. Furthermore, by using similitude analysis the results obtained from small-scale experiments can be applied to full-scale problems. It has been clearly shown that an exploding wire system offers an inexpensive, repeatable, safe, easy to operate, and effective experimental tool for studying phenomena involving blast-structure interactions.

2017

1. Exploration of Methods in the Exploding Wire Technique for Simulating Large Blasts

   Nof, E., Ram, O., Kochavi, E., Ben-Dor, G., and Sadot, O.

   In 30th International Symposium on Shock Waves 2 Mar 2017

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   Small-scale modeling of explosive events has become an important tool in the investigation of blast wave-structure interactions. In this approach, a full-scale model is miniaturized and subjected to "gram-scale" explosions from detonated micro-charges. While offering a cheaper, faster, and ultimately more manageable alternative to full-scale field tests, small-scale testing also offers better reliability and accuracy in more complex scenarios where numerical simulations become limited. Nevertheless, small-scale experiments introduce other difficulties due to the reliance on the well-known Cranz-Hopkinson “cube-root” scaling law. This scaling relationship is suitable for self-similar open-field experiments but does not necessarily apply to urban scenarios. Additionally, chemical explosive charges of such small quantities might be susceptible to changes in parameters such as the explosive compound compression strength, the humidity of the explosive and of the surrounding atmosphere, the method of ignition, etc. Logistically, the handling and preparing of the experimental setup with these small chemical explosives requires specially trained personnel and permits. To overcome these challenges, the exploding wire (EW) technique offers an elegant substitute to using small chemical charges in scaled-down modeling.

2016

1. Dependence of the blast load penetrating into a structure on initial conditions and internal geometry

   Ram*, O.,  Nof*, E., and Sadot, O.

   Experimental Thermal and Fluid Science Mar 2016

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   An experimental study investigated the dependence of the blast load penetrating into a structure on initial conditions and internal geometry. The imposed pressure and impulse profiles at the structures’ frontal façades were varied to generate initial conditions with very different pressures but similar peak impulses to which structural models of varying complexity were exposed. Results show that the peak impulse recorded at the models’ back wall, the target wall, is independent of internal geometry. However, the pressure profiles at the target wall depend heavily on internal geometry in terms of both peak overpressure and wave diffraction pattern. Moreover, the pressure profile developed inside the structure depends strongly on the imposed impulse rather than the imposed pressure profile at the frontal façade. Repeated reflections inside the structure were found to effectively filter out high-frequency pressure changes inside the structure, leading to the possibility of rapid prediction tools for more complex structures. For the first time, a strong indication was found that a scalable time constant can be attributed to a complex structure that characterizes the load developing inside. Based on these findings, an application is presented in which forming a similar impulse is sufficient for correctly simulating large explosions in scaled-down models.

   @article{ram2016depend,
     title = {Dependence of the blast load penetrating into a structure on initial conditions and internal geometry},
     author = {Ram*, O. and Nof*, E. and Sadot, O.},
     bibtex_show = {true},
     journal = {Experimental Thermal and Fluid Science},
     volume = {78},
     pages = {65--74},
     year = {2016},
     publisher = {Elsevier},
     html = {https://doi.org/10.1016/j.expthermflusci.2016.05.012},
     pdf = {2016_Ram_Dependence.pdf}
   }