Experimental Evaluation of Dry Powder Inhalers During In- and Exhalation Using a Model of the Human Respiratory System (xPULM™)

Dry powder inhalers are used by a large number of patients worldwide to treat respiratory diseases. The objective of this work is to experimentally investigate changes in aerosol particle diameter and particle number concentration of pharmaceutical aerosols generated by five dry powder inhalers under realistic inhalation and exhalation conditions. The active respiratory system model (xPULM™) was used as a model of the human respiratory system and to simulate a patient undergoing inhalation therapy. A mechanical upper airway model was developed, manufactured and introduced as a part of the xPULM™ to represent the human upper respiratory tract with high fidelity. Integration of optical aerosol spectrometry technique into the setup allowed for evaluation of pharmaceutical aerosols. The results show that the upper airway model increases the resistance of the overall system and act as a filter for bigger particles (>3 µm). Furthermore, there is a significant difference (p < 0.05) in mean particle diameter between inhaled and exhaled particles with the majority of the particles depositing in the lung. The minimum deposition is reached for particle size of 0.5 µm. The mean particle number concentrations exhaled are 2.94% (BreezHaler®), 2.66% (Diskus®), 10.24% (Ellipta®) 2.13% (HandiHaler®) and 6.22% (Turbohaler®). In conclusion, the xPULM™ active respiratory system model is a viable option for studying interactions of pharmaceutical aerosols and the respiratory tract in terms of applicable deposition mechanisms. The model can support the reduction of animal experimentation in aerosol research and provide an alternative to experiments with human subjects.

A report on virtual ‘Can’t intubate, can’t oxygenate’ conference workshops at the 2021 Annual Scientific Meeting of the Australian and New Zealand College of Anaesthetists

The COVID-19 pandemic has had profound implications for continuing medical education. Travel restrictions, lockdowns and social distancing in an effort to curb spread have meant that medical conferences have been postponed or cancelled. When the Australian and New Zealand College of Anaesthetists made the decision to commit to a fully virtual 2021 Annual Scientific Meeting, the organising committee investigated the viability of presenting a virtual ‘Can’t intubate, can’t oxygenate’ workshop. A workshop was designed comprising a lecture, case scenario discussion and demonstration of emergency front-of-neck access techniques broadcast from a central hub before participants separated into Zoom® (Zoom Video Communications, San Jose, CA, USA) breakout rooms for hands-on practice, guided by facilitators working virtually from their own home studios. Kits containing equipment including a 3D printed larynx, cannula, scalpel and bougie were sent to workshop participants in the weeks before the meeting. Participants were asked to complete pre- and post-workshop surveys. Of 42 participants, 32 responded, with the majority rating the workshop ‘better than expected’. All except two respondents felt the workshop met learning objectives. Themes of positive feedback included being impressed with the airway model, the small group size, content and delivery. Feedback focused on previously unperceived advantages of virtual technical skills workshops, including convenience, equitable access and the reusable airway model. Disadvantages noted by respondents included lack of social interaction, inability to trial more expensive airway equipment, and some limitations of the ability of facilitators to review participants’ technique. Despite limitations, in our experience, virtual workshops can be planned with innovative solutions to deliver technical skills education successfully.

Niclosamide shows strong antiviral activity in a human airway model of SARS-CoV-2 infection and a conserved potency against the Alpha (B.1.1.7), Beta (B.1.351) and Delta variant (B.1.617.2)

SARS-CoV-2 variants are emerging with potential increased transmissibility highlighting the great unmet medical need for new therapies. Niclosamide is a potent anti-SARS-CoV-2 agent that has advanced in clinical development. We validate the potent antiviral efficacy of niclosamide in a SARS-CoV-2 human airway model. Furthermore, niclosamide remains its potency against the D614G, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants. Our data further support the potent anti-SARS-CoV-2 properties of niclosamide and highlights its great potential as a therapeutic agent for COVID-19.

TRANSITION AND LAMINAR FLOWS IN A REALISTIC GEOMETRY OF HUMAN UPPER AIRWAY

In this study, a realistic respiratory airway model extending from oral to the end of the trachea including all the key details of the passage was produced. A series of CT scan images were used to generate the topological data of airway cross-sections that were used to generate the computational model, as well as the three-dimensional (3D) printed model of the passage for experimental study. The airflow velocity field and pressure drop in the airway for different breathing rates of 5, 7.5, 10, and 12.5[Formula: see text]L/min were investigated numerically (by laminar and transition models) and experimentally. The velocity distributions, pressure variation, and streamlines along the oral–trachea airway model were studied. The maximum pressure drop was shown to occur in the narrowest part of the larynx region. It was also concluded that the laryngeal jet could significantly influence the airway flow patterns in the trachea. A comparison between the numerical results and experimental data showed that the transition [Formula: see text]–kl–[Formula: see text] model can give better predictions of pressure losses, especially for flow rates higher than 10[Formula: see text]L/min. The simulation results for the velocity profiles in the trachea were also compared with the available particle image velocimetry (PIV) data and earlier simulations. Despite inter-personal variability and difference in the flow regime, the qualitative agreement was found.

Experimental Evaluation of Dry Powder Inhalers During In- and Exhalation Using a Model of the Human Respiratory System (xPULM™)

Dry powder inhalers are used by a large number of patients worldwide to treat respiratory diseases. The objective of this work is to experimentally investigate changes in aerosol particle diameter and particle number concentration of pharmaceutical aerosols generated by five dry powder inhalers under realistic inhalation and exhalation conditions. The active respiratory system model (xPULM™) was used as a model of the human respiratory system and to simulate a patient undergoing inhalation therapy. A mechanical upper airway model was developed, manufactured and introduced as a part of the xPULM™ to represent the human upper respiratory tract with high fidelity. Integration of optical aerosol spectrometry technique into the setup allowed for evaluation of pharmaceutical aerosols. The results show that the upper airway model increases the resistance of the overall system and act as a filter for bigger particles (>3 µm). Furthermore, there is a significant difference (p < 0.05) in mean particle diameter between inhaled and exhaled particles with the majority of the particles depositing in the lung. The minimum deposition is reached for particle size of 0.5 µm. The mean particle number concentrations exhaled are 2.94% (BreezHaler®), 2.66% (Diskus®), 10.24% (Ellipta®) 2.13% (HandiHaler®) and 6.22% (Turbohaler®). In conclusion, the xPULM™ active respiratory system model is a viable option for studying interactions of pharmaceutical aerosols and the respiratory tract in terms of applicable deposition mechanisms. The model can support the reduction of animal experimentation in aerosol research and provide an alternative to experiments with human subjects.

Direct Transcriptomic Comparison of Xenobiotic Metabolism and Toxicity Pathway Induction of Airway Epithelium Models at an Air Liquid Interface Generated from Induced Pluripotent Stem Cells and Primary Bronchial Epithelial Cells

The airway epithelium represents the main barrier between inhaled air and the tissues of the respiratory tract and is therefore an important point of contact with xenobiotic substances into the human body. Several studies have recently shown that in vitro models of the airway grown at an air liquid interface (ALI) can be particularly useful to obtain mechanistic information about the toxicity of chemical compounds. However, such methods are not very amenable to high throughput since the primary cells cannot be expanded indefinitely in culture to obtain a sustainable number of cells. Induced pluripotent stem cells (iPSCs) have become a popular option in the recent years for modelling the airways of the lung, but despite progress in the field, such models have so far not been assessed for their ability to metabolise xenobiotic compounds and how they compare to the primary bronchial airway model (pBAE). Here we report a comparative analysis by TempoSeq (oligo directed sequencing) of an iPSC derived airway model (iBAE) with a primary bronchial airway model (pBAE). The iBAE and pBAE were differentiated at an ALI and then evaluated in a 5-compound screen with exposure to a sub lethal concentration of each compound for 24 hours. We found that despite lower expression of xenobiotic metabolism genes, that the iBAE similarly predicted the toxic pathways when compared to the pBAE model. Our results show that iPSC airway models at ALI show promise for inhalation toxicity assessments with further development.