Pulmonary Aerosol Research Articles

Aerosol dosimetry in the whole conducting zone of a murine left-lung using CF-PD and LSFM images

Aerosol dosimetry in respiratory airways is relevant for pulmonary drug delivery and inhalation toxicology. Consequently, computational fluid-particle dynamics (CF-PD) modelling of pulmonary aerosol delivery is an active research field. Additionally, mice are the most commonly used animals in medical research. Technological advances have provided information on whole mice lung morphologies with unprecedented high resolution. Therefore, in this study, we used high-resolution light sheet fluorescent microscopy (LSFM) images of a healthy C57BL/6 mouse lung with a constant air flow rate of 72 ml/min, to extract an anatomical 3-dimensional (3D) geometry of the entire airway tree of the left lung from the primary bronchi to the most distal bronchioles excluding the trachea. The airways were segmented based on an order- and generation-based method. Also, to compare the morphological data and regional deposition, a generation-based investigation including 25 generations was employed in the present model. One-way coupling of CF-PD modeling was applied to model an intubated and mechanically-ventilated mouse. Maximum values of the velocity and vorticity magnitude of 3.2 m/s and 200,000 1/s were reached in the second order, respectively, and maximum pressure and wall shear stress levels were 30 Pa and 3.5 Pa, respectively. Finally, order- and generation-based particle deposition efficiency and dose per lung area were obtained for the particle size range of 1 μm ≤ dp ≤ 10 μm yielding pronounced hotspot deposition patterns mainly near the proximal bifurcations. The results showed a positive correlation between deposition efficiency and particle size due to a size-dependent increase in inertial and gravitational effects. Maximum regional deposition and normalized dose was seen for 10 μm particles in the 1st order of the murine left lung. Smaller peak sizes of deposition efficiency were seen in the third and fourth orders of the mouse left lung due to almost complete loss of the largest particles in lower order airways. It also justifies the close to zero deposition efficiency in the highest orders (fifth to sixth). Both lung morphology as well as total and regional aerosol deposition showed reasonably good agreement with empirical data from the literature. The present CF-PD model with accurate realistic lung morphology, improves our knowledge of airway aerosol deposition hotspots. The obtained modeling method and the qualitative results can be implemented on human airways.

Recent Developments in Aerosol Pulmonary Drug Delivery: New Technologies, New Cargos, and New Targets.

There is nothing like a global pandemic to motivate the need for improved respiratory treatments and mucosal vaccines. Stimulated by the COVID-19 pandemic, pulmonary aerosol drug delivery has seen a flourish of activity, building on the prior decades of innovation in particle engineering, inhaler device technologies, and clinical understanding. As such, the field has expanded into new directions and is working toward the efficient delivery of increasingly complex cargos to address a wider range of respiratory diseases. This review seeks to highlight recent innovations in approaches to personalize inhalation drug delivery, deliver complex cargos, and diversify the targets treated and prevented through pulmonary drug delivery. We aim to inform readers of the emerging efforts within the field and predict where future breakthroughs are expected to impact the treatment of respiratory diseases.

1704. Epetraborole, a Novel Bacterial Leucyl-tRNA Synthetase Inhibitor, Demonstrates Potent Efficacy and Improves Efficacy of Standard of Care Regimen Against Mycobacterium avium complex in a Chronic Mouse Lung Infection Model

Abstract Background Epetraborole (EBO) is a boron-containing oral inhibitor of bacterial leucyl-tRNA synthetase, an essential enzyme in protein synthesis; EBO demonstrates potent activity against nontuberculous mycobacteria. These studies evaluated oral doses (PO) of EBO against 5 M. avium complex (MAC) strains in a chronic mouse infection model either as monotherapy or in combination with standard of care [SOC; clarithromycin (CLR), rifabutin (RFB), ethambutol (EMB)]. Methods A pilot chronic efficacy study against M. avium 2285R evaluated EBO at 1, 10, 30, 100, 300 and 500 mg/kg PO once daily (QD) compared to 250 mg/kg CLR PO QD. C57BL/6 mice were infected with a pulmonary aerosol of 1x1011 CFU. Treatment was administered for 56 days starting on day 28 post-infection. The bacterial burden (CFU) in lungs was evaluated on days 1, 28 and 84 post-infection by plating serial dilutions of homogenates on Middlebrook 7H11 charcoal agar plates. An additional 4 strains of MAC were evaluated with EBO doses of 100, 200, 300 or 400 mg/kg QD compared with the SOC therapy for MAC (CLR 250 mg/kg, RFB 100 mg/kg, EMB 100 mg/kg) QD and SOC plus EBO 200mg/kg QD. Oral exposures of EBO were determined in a group of uninfected mice (Table 1).Table 1:C57BL/6 Murine Pharmacokinetic Parameters Results In a study with M. avium 2285R, a biofilm-forming strain, EBO at all doses tested was significantly better than CLR dosed at 250 mg/kg (Figure 1), and no CFU were detected on agar plates containing EBO (16 mg/L). In subsequent studies, SOC was compared to EBO in 4 additional MAC strains (Figure 2). Efficacy of EBO monotherapy was better than SOC against M. avium ATCC 700898, while it was as good as SOC with M. intracellulare 1956, M. intracellulareDNA00055, and M. intracellulare DNA00111 with CFU reductions ranging from 2 - 4.8 log10 compared to day 28 controls. In all four strains tested, 200 mg/kg EBO, which approximates the human oral equivalent dose of 500 mg, combined with SOC increased bacterial killing from 1.4 - 3.0 log10 CFU compared to SOC alone resulting in total lung CFU reductions of 4.6 - 5.6 log10. Figure 1Figure 2 Conclusion In this chronic mouse lung infection model, no EBO resistance development was detected with M. avium 2285R at day 84. EBO demonstrated potent in vivo efficacy against 5 MAC strains and significantly improved efficacy when combined with SOC, supporting further clinical development for EBO. Disclosures Michelle S. DeStefano, n/a, AN2 Therapeutics: Grant/Research Support Carolyn Shoen, PhD, AN2 Therapeutics: Grant/Research Support Michael H. Cynamon, MD, AN2: Grant/Research Support|AN2: Grant/Research Support MRK Alley, PhD, ABBOTT LABS: Stocks/Bonds|ABBVIE: Stocks/Bonds|AN2 Therapeutics: Author on epetraborole patent|AN2 Therapeutics: Salary|AN2 Therapeutics: Ownership Interest|AVANOS MED INC: Stocks/Bonds|NABRIVA THERAPEUTICS PLC: Stocks/Bonds|NOVARTIS AG: Stocks/Bonds.

A Novel Machine Learning Prediction Model for Aerosol Transport in Upper 17-Generations of the Human Respiratory Tract

The main challenge of the health risk assessment of the aerosol transport and deposition to the lower airways is the high computational cost. A standard large-scale airway model needs a week to a month of computational time in a high-performance computing system. Therefore, developing an innovative tool that accurately predicts transport behaviour and reduces computational time is essential. This study aims to develop a novel and innovative machine learning (ML) model to predict particle deposition to the lower airways. The first-ever study uses ML techniques to explore the pulmonary aerosol TD in a digital 17-generation airway model. The ML model uses the computational data for a 17-generation airway model and four standard ML regression models are used to save the computational cost. Random forest (RF), k-nearest neighbour (k-NN), multi-layer perceptron (MLP) and Gaussian process regression (GPR) techniques are used to develop the ML models. The MLP regression model displays more accurate estimates than other ML models. Finally, a prediction model is developed, and the results are significantly closer to the measured values. The prediction model predicts the deposition efficiency (DE) for different particle sizes and flow rates. A comprehensive lobe-specific DE is also predicted for various flow rates. This first-ever aerosol transport prediction model can accurately predict the DE in different regions of the airways in a couple of minutes. This innovative approach and accurate prediction will improve the literature and knowledge of the field.

Pulmonary Aerosol Delivery of Let-7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune Microenvironment.

MicroRNAs are potential candidates for lung cancer prevention and therapy. A major limitation is the lack of an efficient delivery system to directly deliver miRNA to cancer cells while limiting systemic exposure. The delivery of miRNA via inhalation is a potential strategy for lung cancer prevention in high‐risk individuals. In this study, the authors investigate the efficacy of aerosolized let‐7b miRNA treatment in lung cancer prevention. Let‐7b shows significant inhibition of B[a]P‐induced lung adenoma with no detectable side effects. Single‐cell RNA sequencing of tumor‐infiltrating T cells from primary tumors reveals that Let‐7b post‐transcriptionally suppresses PD‐L1 and PD‐1 expression in the tumor microenvironment, suggesting that let‐7b miRNAs may promote antitumor immunity in vivo. Let‐7b treatment decreases the expression of PD‐1 in CD8+ T cells and reduces PD‐L1 expression in lung tumor cells. The results suggest that this aerosolized let‐7b mimic is a promising approach for lung cancer prevention, and that the in vivo tumor inhibitory effects of let‐7b are mediated, at least in part, by immune‐promoting effects via downregulating PD‐L1 in tumors and/or PD‐1 on CD8+ T cells. These changes potentiate antitumor CD8+ T cell immune responses, and ultimately lead to tumor inhibition.

Narrative review of practical aspects of aerosol delivery via high-flow nasal cannula.

Using high-flow nasal cannula (HFNC) as a "vehicle" to administer aerosolized medication has attracted clinicians' interest in recent years. In this paper, we summarize the current evidence to answer the common questions raised by clinicians about this new aerosol delivery route and best practices of administration. Benefits of trans-nasal aerosol delivery include increased comfort, ability to speak, eat, and drink for patients while meeting a range of oxygen requirements, particularly for those who need to inhale aerosolized medication for long periods. Aerosol administration via HFNC has been shown to be well tolerated by children and adults, with comparable or better delivery efficacy than other interfaces, ranging from 2-20%. In vitro and in vivo scintigraphy studies among pediatric and adult populations reported that the inhaled dose delivered via a vibrating mesh nebulizer is 2 to 3 fold greater than that via a jet nebulizer. For adults, placement of nebulizer at the inlet of humidifier increases inhaled dose while reducing rainout obstructing nasal prongs. When HFNC gas flow is set below patient inspiratory flow, aerosol deposition is higher than when the gas flow exceeds patient inspiratory flow; thus, if tolerated, titrating down HFNC gas flow during trans-nasal aerosol delivery, with close monitoring and the use of unit dose with high concentration are recommended. Trans-nasal pulmonary aerosol delivery has not been shown to increase bioaerosols generated by patients, but gas flow may disperse aerosols. Placement of a surgical or procedure mask over HFNC might reduce aerosol dispersion.

1635. Oral Delivery of Amikacin-Lipid NanoCrystal Formulations Safely and Effectively Treat Macrolide Resistant Mycobacteria Infections in a Mouse Model of Cystic Fibrosis

BackgroundIn the cystic fibrosis lung, infections by intracellular pathogens, such as Mycobacteria, are problematic to treat due to a thick buildup of mucous as well as the difficulty of many anti-microbial agents, such as amikacin, to penetrate across the plasma membranes of infected cells. Lipid NanoCrystals (LNCs), mediate oral bioavailability for injectable drugs, reduce toxicity, and significantly enhance targeting to mycobacterial infected cells followed by intracellular drug delivery.MethodsThe oral efficacy of Amikacin-LNC (AmK-LNC) was evaluated in the cystic fibrosis (B6CFTRtm1UNC/CFTRtm1UNC) chronic mouse model against each of the three NTM strains having high resistance to macrolide antibiotics (M. avium subsp intracellulare 25292, M. abscesus ssp abscessus 1513, and M. abscessus ssp bolletii 1948). Mice were infected with a pulmonary aerosol of 1x108 CFUs of the macrolide resistant strain and treated daily starting on day 28 for a total of 8 weeks with saline control, oral LP-4 CAmK Lyophilized 50 mg/kg BID, oral LP-4 CAMK Lyophilized 100 mg/kg BID, IP Amikacin (AMI) 150 mg/kg QD, or oral Clarithromycin 250 mg/kg QD. Bacterial burden was measured on day 1, 27, 42, 56 and 84 after infection by plating serial dilutions of organ homogenates on nutrient 7H11 and charcoal agar and counting CFUs after 25-30 days incubation at 32°C. Results represent the average of six experiments (n=5 mice per experiment) bacterial load was expressed as the average Log10 CFU (± SEM) cells (± SEM). ANOVA, saline control compared to drug-treated groups, * denotes the compound that resulted in the highest bacterial reduction, *p< 0.05.ResultsOral administration of AmK-LNCs safely and effectively treated all three macrolide resistant Mycobacteria infections. Colony counts showed that oral administration of AmK-LNC resulted in CFU lung, spleen and liver counts lower than treatment with IP amikacin or clarithromycin.Lung pathology showed that lesions were more numerous and larger in infected mice treated with clarithromycin or amikacin compared to the smaller lesions after treatment with oral AmK-LNC.Bacterial Counts in the Lungs (A), Spleens (B) and Livers (C) Lung Pathology ConclusionConclusionsOral administration of amikacin-LNCs safely and effectively treats macrolide resistant mycobacterial infections in a mouse model of Cystic Fibrosis.DisclosuresRuying Lu, n/a, Matinas BioPharma Inc. (Employee)Matinas BioPharma Inc. (Employee, Shareholder) Raphael J. Mannino, n/a, Matinas BioPharma Inc. (Employee, Shareholder)

1637. SPR720, A Novel Benzamidazole Gyrase Inhibitor, Demonstrates Potent Efficacy Against Mycobacterium avium ATCC 700898 in a Chronic C3HeBFeJ Mouse Infection Model

BackgroundSPR719 (the active metabolite of phosphate prodrug SPR720) belongs to a novel class which targets the ATPase subunits of gyrase by a mechanism distinct from fluoroquinolones. SPR719 has potent antibacterial activity against nontuberculous mycobacteria strains (NTM), including Mycobacterium avium, and is under development for treatment of NTM pulmonary disease. Oral efficacy of SPR720 was evaluated alone and in combination treatment in the C3HeBFeJ chronic mouse infection model which produces necrotic granulomas, similar to humans.MethodsMice were infected with a pulmonary aerosol of 1x108.5 CFU of M. avium ATCC 700898, (SPR719 MIC = 2 mg/mL). Treatment started on day 28 for 8 weeks with: saline, clarithromycin 250 mg/kg (CLR) QD, SPR720 at 10, 30 and 100 mg/kg QD, or SPR720 at 50 mg/kg BID. SPR720 at 30 mg/kg QD was also combined with CLR +/- ethambutol at 100 mg/kg (EMB), or CLR + rifabutin at 100 mg/kg (RFB) +/- EMB. Mice were evaluated for bacterial burden (CFU) on days 1, 27 and 60 after infection by plating serial dilutions of organ homogenates on nutrient 7H11 and charcoal agar plates. Lung pathology was evaluated by assessing prevalence and size of pulmonary lesions.ResultsCLR treatment for 28 days showed a significant reduction in the bacterial burden in the lung, spleen, and liver compared to the untreated control. SPR720 demonstrated a dose dependent reduction in bacterial burden, including at 100 mg/kg which showed a statistically significant reduction in the bacterial burden in the lung, spleen, and liver. CLR + EMB + SPR720 at 30 mg/kg reduction in the bacterial burden in the lung, spleen, and liver. RFB when added to the treatment regimen did not demonstrate enhanced efficacy compared the additive effect of EMB + CLR +/- SPR720. Lung pathology showed that lesions were less numerous and smaller in infected mice treated with all regimens.ConclusionOral administration of SPR720 demonstrated a statistically significant reduction in the bacterial burden in all tissues with concomitant improvement in lung pathology, both alone and in combination with standard of care agents. These results support the continued development of SPR720 for treatment of NTM pulmonary infections.DisclosuresNicole S. Cotroneo, BS, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder)

Biodistribution and acute toxicity of cadmium-free quantum dots with different surface functional groups in mice following intratracheal inhalation.

Indium phosphide/zinc sulfate (InP/ZnS) quantum dots (QDs) are presumed to be less hazardous than those that contain cadmium. However, the toxicological profile has not been established. The present study investigated the acute toxicity of InP/ZnS QDs with different surface modifications (COOH, NH2, and OH) in mice after pulmonary aerosol inhalation. InP/ZnS QDs were able to pass through the blood-gas barrier and enter the circulation, and subsequently accumulated in major organs. No obvious changes were observed in the body weight or major organ coefficients. Red blood cell counts and platelet-related indicators were in the normal range, but the proportion of white blood cells was altered. The InP/ZnS QDs caused varying degrees of changes in some serum markers, but no histopathological abnormalities related to InP/ZnS QDs treatment was observed in major organs except that hyperemia in alveolar septa was found in lung sections. These results suggested that the effects of respiratory exposure to InP/ZnS QDs on the lungs need to be fully considered in future biomedical application although the overall toxicity of quantum dots is relatively low.

In vitro comparison of unit dose vs infusion pump administration of albuterol via high-flow nasal cannula in toddlers.

Transnasal pulmonary aerosol delivery using high-flow nasal cannula (HFNC) devices has become a popular route of aerosol administration in toddlers. Clinically, albuterol is administered using an infusion pump or unit doses. However, little evidence is available to compare the two administration strategies. A toddler manikin (15 kg) with appropriate anatomic airway was connected with collecting filter to a simulator of distressed breathing. HFNC device with mesh nebulizer placed at the inlet of a humidifier at 37°C, with the gas flow set at 25 and 3.75 L/min. Five milligrams of albuterol was delivered in all experiments. With infusion pump administration, albuterol concentrations of 5 and 1 mg/mL were delivered at 4 and 20 mL/hr for 15 minutes. With unit dose administration, 1 mL (5 mg/mL) and 2 mL (2.5 mg/mL) of albuterol were nebulized. Additional tests with mouth open and nebulizers via mask were using 5 mg/1 mL for mesh nebulizer and 5 mg/3 mL for jet nebulizer (n = 3). The drug was eluted from the filter and assayed with UV spectrophotometry (276 nm). The inhaled dose was higher with unit dose than infusion pump administration with gas flows of 25 L/min (2.66 ± 0.38 vs 1.16 ± 0.28%; P = .004) and 3.75 L/min (10.51 ± 1.29 vs 8.58 ± 0.68%; P = .025). During unit dose administration, compared with closed-mouth breathing, open-mouth breathing generated a higher inhaled dose at 3.75 L/min and lower inhaled dose at 25 L/min. Compared to the nebulizers via mask with both open and closed-mouth breathing, nebulization via HFNC at 3.75 L/min generated greater inhaled dose, while HFNC at 25 L/min generated lower inhaled dose. During transnasal aerosol delivery, the inhaled dose was higher with medication administrated using unit dose than using an infusion pump.

Dose Response to Transnasal Pulmonary Administration of Bronchodilator Aerosols via Nasal High-Flow Therapy in Adults with Stable Chronic Obstructive Pulmonary Disease and Asthma

Background: There has been increasing interest in transnasal pulmonary aerosol administration, but the dose-response relationship has not been reported. Objectives: To determine the accumulative bronchodilator dose at which patients with stable mild-to-moderate asthma and chronic obstructive pulmonary disease (COPD) achieve similar spirometry responses before and after bronchodilator tests using albuterol via a metered dose inhaler with a valved holding chamber (MDI + VHC). Method: Adult patients who met ATS/ERS criteria for bronchodilator responses in pulmonary function laboratory were recruited and consented to participate. After a washout period, patients received escalating doubling dosages (0.5, 1, 2, and 4 mg) of albuterol in a total volume of 2 mL delivered by vibrating mesh nebulizer via a nasal cannula at 37°C with a flow rate of 15–20 L/min using a Venturi air entrainment device. Spirometry was measured at baseline and after each dose. Titration was stopped when an additional forced expiratory volume in 1 second (FEV₁) improvement was <5%. Results: 42 patients (16 males) with stable mild-to-moderate asthma (n = 29) and COPD (n = 13) were enrolled. FEV₁ increment after a cumulative dose of 1.5 mg of albuterol via nasal cannula at 15–20 L/min was similar to 4 actuations of MDI + VHC (0.34 ± 0.18 vs. 0.34 ± 0.12 L, p = 0.878). Using ATS/ERS criteria of the bronchodilator test, 33.3% (14/42) and 69% (29/42) of patients responded to 0.5 and 1.5 mg of albuterol, respectively. Conclusions: With a nasal cannula at 15–20 L/min, transnasal pulmonary delivery of 1.5 mg albuterol resulted in similar bronchodilator response as 4 actuations of MDI + VHC.

Impact of Gas Flow and Humidity on Trans-Nasal Aerosol Deposition via Nasal Cannula in Adults: A Randomized Cross-Over Study.

Background: Trans-nasal pulmonary aerosol delivery using high flow nasal cannula (HFNC) devices is described with the administration of high gas flows exceeding patient inspiratory flow (HF) and with lower flows (LF). The aim of this pilot clinical trial was to compare deposition and distribution of radiolabeled aerosol via nasal cannula in healthy adults across three rates of gas flow delivered with active heated humidification, and to further identify the impact of aerosol administration without heated humidity. Methods: Twenty-three (23) healthy adults (16F) were randomized to receive aerosol with active heated humidification or unheated oxygen at gas flows of 10 L/min (n = 8), 30 L/min (n = 7), or 50 L/min (n = 8). Diethylenetriaminepentaacetic acid labeled with 1 millicurie (37 MBq) of Technetium-99m (DTPA-Tc99m) was mixed with NaCl to a fill volume of 1 mL, and administered via mesh nebulizer placed at the inlet of the humidifier. Radioactivity counts were performed using a gamma camera and the regions of interest (ROIs) were delimited with counts from the lungs, upper airways, stomach, nebulizer, circuit, and expiratory filter. A mass balance was calculated and each compartment was expressed as a percentage of the total. Results: Lung deposition (mean ± SD) with heated humidified gas was greater at 10 L/min than 30 L/min or 50 L/min (17.2 ± 6.8%, 5.71 ± 2.04%, and 3.46 ± 1.24%, respectively; p = 0.0001). Using unheated carrier gas, a lung dose of aerosol was similar to the active heated humidification condition at 10 L/min, but greater at 30 and 50 L/min (p = 0.011). Administered gas flow and lung deposition were negatively correlated (r = −0.880, p < 0.001). Conclusions: Both flow and active heated humidity inversely impact aerosol delivery through HFNC. Nevertheless, aerosol administration across the range of commonly used flows can provide measurable levels of lung deposition in healthy adult subjects (NCT 02519465).

Effects of flow rate on transnasal pulmonary aerosol delivery of bronchodilators via high-flow nasal cannula for patients with COPD and asthma: protocol for a randomised controlled trial

IntroductionBoth in vitro and in vivo radiolabelled studies on nebulisation via high-flow nasal cannula showed that inhaled dose decreases as the administered gas flow increases. In our previous in vitro...

Deposition studies of aerosol delivery by nasal cannula to infants.

Nasal cannulas are used to provide oxygen support for infants and have been considered as a means for delivering aerosols to the lungs. To measure mucociliary clearance in the lungs of infants with congenital heart defects, we delivered radiopharmaceutical aerosols via a nasal cannula. Here we report on the pulmonary and nasal deposition of these aerosols. A total of 18 infants (median age = 26 days; quartiles = 11-74 days) performed clearance measurements soon before or after corrective cardiac surgery. The regional aerosol deposition was assessed using gamma camera imaging. Cannula flow rate significantly affected pulmonary dosing. Flow rates useful for oxygen support were associated with low pulmonary deposition (2 L/min; mean, 4.5% of deposited dose; range, 2%-9%; n = 7) and high nasal deposition. Much lower cannula flow rates increased the pulmonary deposition (0.2 L/min; mean, 33.5% of deposited dose; range, 15%-51%; n = 5; P = 0.005 vs 2 L/min). The ratio of nose/lung dosing was approximately 26:1 at 2 L/min and 2:1 at 0.2 L/min. Bench studies demonstrated cannula output rates of 10.2 ± 1.7% (2 L/min) and 3.3 ± 0.4% (0.2 L/min) of the loaded nebulizer dose during a 2-minute delivery. Combining in vitro and in vivo results, we estimate that 0.46% of the loaded nebulizer dose reaches the lungs at 2 L/min vs 1.10% at 0.2 L/minduring a 2-minute delivery. With the delivery system used here, pulmonary aerosol delivery via nasal cannula was very inefficient at the flow rates required to provide oxygen support. Even at low flows, nasal deposition was substantial and local toxicity must be considered.

Decrease the flow setting to improve trans-nasal pulmonary aerosol delivery via "high-flow nasal cannula" to infants and toddlers.

Trans-nasal pulmonary aerosol delivery for infants and toddlers has recently gained popularity, however, the reported lung deposition is low. We aimed to investigate the influential factors to improve the delivery. Anatomic airway manikins simulating infant (5 kg) and toddler (15 kg) with collecting filter connected the trachea and breath simulator, were set to represent quiet and distressed breathing. Nasal cannula flow was set at 0.125, 0.25, 0.5, 1, and 2 L/kg/min. A mesh nebulizer (Aerogen) was placed at the inlet of humidifier (Fisher & Paykel) and proximal to patient. Albuterol (5 mg in 1 mL) was nebulized for each condition (n = 3). Drug was eluted from the filter and assayed with UV spectrophotometry (276 nm). Inhaled dose was higher with nebulizer placed at the inlet of humidifier than proximal to patient in all settings, except the infant model at low gas flow settings (0.125 and 0.25 L/kg/min). When nebulizer was placed at the inlet of humidifier, inhaled dose was higher when gas flow was below patient's inspiratory flow than when gas flow exceeded patient's inspiratory flow (8.77 ± 3.84 vs 2.16 ± 1.29%, P < 0.001); aerosol deposition increased as gas flow decreased, with greatest deposition at gas flow of 0.25 L/kg/min (11.29 ± 2.15%). A multiple linear regression identified gas flow as the primary predictor of aerosol delivery. Trans-nasal pulmonary aerosol delivery was significantly improved when gas flow was below patient's inspiratory flow, aerosol deposition increased with decreased nasal cannula flow, with greatest deposition at 0.25 L/kg/min.

Euler–Lagrange approach to investigate respiratory anatomical shape effects on aerosol particle transport and deposition

An accurate knowledge of the pulmonary aerosol particle transport in the realistic lung is essential to deliver the therapeutic particle to the targeted site of the bifurcating airways. The available in silico studies have enriched the knowledge of the aerosol transport and deposition (TD) in the lung; however, the absolute TD data in the realistic lung airway are still elusive. Therefore, in this study, a 3-D geometry of the human lung central airway is developed from the computed tomography (CT) images. A CT scan-based modified lung geometry with a smooth surface and nonrealistic Weibel’s lung geometry is also generated. The coal mine exhausted aerosol TD in the upper airway is investigated. The Euler–Lagrange (E-L) method for particle tracking and ANSYS Fluent solver are used to carry out the entire investigation. The effective diameter method is employed to define the shape-specific particles and is integrated with the E-L method. The anatomical shape effects on the deposition patterns are investigated for different deposition parameter. The numerical results illustrated that the airway geometry, particle shape, particle diameter, and breathing flow rates significantly influence the aerosol TD pattern in the upper airway. The present study reports that airway tracheal wall is the new deposition hot spot for the CT-based geometry instead of bifurcating area for the idealized model, which might be helpful for zone-specific drug delivery to the respiratory airways.

Pulmonary aerosol delivery and the importance of growth dynamics.

Aerosols are dynamic systems, responding to variations in the surrounding environmental conditions by changing in size, composition and phase. Although, widely used in inhalation therapies, details of the processes occurring on aerosol generation and during inhalation have received little attention. Instead, research has focused on improvements to the formulation of the drug prior to aerosolization and the resulting clinical efficacy of the treatment. Here, we highlight the processes that occur during aerosol generation and inhalation, affecting aerosol disposition when deposited and, potentially, impacting total and regional doses. In particular, we examine the response of aerosol particles to the humid environment of the respiratory tract, considering both the capacity of particles to grow by absorbing moisture and the timescale for condensation to occur.

Overnight delivery of hypertonic saline by nasal cannula aerosol for cystic fibrosis.

Inhaled hypertonic saline increases mucociliary clearance, improves pulmonary function, and decreases exacerbations in cystic fibrosis (CF) but contributes to the already significant treatment burden of CF. Overnight delivery of inhaled medications via a specially designed nasal cannula-aerosol device (Trans-nasal Pulmonary Aerosol Delivery [tPAD]) is an alternative approach. Here, we test whether overnight inhalation of hypertonic saline via tPAD improves mucociliary clearance and assess the tolerability of the device. In this study, 12 CF subjects inhaled 7% hypertonic saline (HS) for 8 h overnight using the tPAD system. Safety and tolerability were assessed and measurements of mucociliary and absorptive clearance (MCC/ABS) were performed after the treatment. Comparisons were made versus sham treatment where the same subjects wore the nasal cannula overnight but did not receive aerosol. Both the HS and sham treatments were well-tolerated. Only one subject did not complete the overnight HS treatment. There were no significant differences in MCC associated with HS inhalation at any time point (90 min, 3 h, 6 h) in any lung zone. Changes in FEV1 on both study days were similar. There were no differences in quality of sleep between HS and sham nights as assessed with the modified Leeds Sleep Evaluation Questionnaire (mLSEQ). Sino-Nasal Outcome Test (SNOT-14) questionnaires demonstrated significant increases (worsening) in 2/14 symptom categories with HS. The most likely cause for the failure to accelerate MCC was under-dosing of HS relative to the active transport of salt from the airways.

Pulmonary aerosol transport and deposition analysis in upper 17 generations of the human respiratory tract

The major problem in understanding the therapeutically targeted drug delivery system in the deeper airways of the human lung is the lack of adequate data of particle transport and deposition (TD) in the transitional and respiratory zones (deeper airways) of the human lung. An understanding of the morphometry of the pulmonary airways and the lungs forms the primary step in a study of pulmonary aerosol deposition. The present study is the first-ever approach to explore the pulmonary aerosol TD in a digital 17-generation human pulmonary airway model. The present numerical study achieved the lack of the particle TD data in the deeper airways of the human lung. This paper presents a 3-D (3-dimensional) CFD (Computational Fluid Dynamics) study of an anatomically realistic 17-generation lung bronchial tree model based on the high-resolution computer tomography (HRCT) data by Schmidt et al. (2004). Physical morphometry is necessary for sufficiently calculating air and particle dynamics in human pulmonary airways with available data on a large number of generations. A Lagrangian-based Discrete Phase Model (DPM) is used to study the particle TD in the 17-generation of the lung airways. The numerical results demonstrate that inertial impaction is dominant in the upper airways and a large percentage of particles is deposited in the upper airways. The numerical results also illustrate that a large percentage of smaller diameter particles leaves through the airway outlet boundary at the 17th generation irrespective of breathing patterns. The escaped particles are considered to continue to follow the airway flow field further downstream after the 17th generation till the 23rd generation and some of them will reach the alveolar sacs region. This computational model could potentially aid in overcoming the nanobiotechnology toxicity problem for drug delivery in the deeper airways.

A Trans-Nasal Aerosol Delivery Device for Efficient Pulmonary Deposition

Efficient delivery of aerosols to the lungs via the nasal route has been difficult to achieve, but it may offer benefits over the traditional oral route for a range of patient populations. Because slow, continuous delivery of short-acting agents could improve safety, tolerability, compliance, and efficacy when compared with the rapid, intermittent aerosol treatments delivered by mouthpiece or mask, a novel trans-nasal pulmonary aerosol delivery (tPAD) device was developed. The tPAD incorporates an aerosol particle-size selection chamber and a custom nasal cannula that are specifically optimized for aerosol delivery to the lung via the nasal route. The tPAD device produced a steady aerosol output (∼2 mL/h) from an optimized nasal cannula with negligible rainout in the cannula for up to 8 hours. The generated aerosol particles were small enough to minimize nasal deposition [volume median diameter (VMD) = 1.4 μm]. In this proof-of-concept study, gamma scintigraphy was used to quantitate deposition efficiency of 99mTc-labeled DTPA in 7% NaCl (hypertonic saline) in healthy human subjects (n = 6) during a short dosing period (15 minutes). A comparison was made with a standard oral jet nebulizer in the same subjects. The tPAD device achieved high pulmonary deposition (39% ± 8%), based on emitted dose, and matched that of the oral jet nebulizer (36% ± 9%). Low fractions of aerosol deposition in the head and nose region were observed for tPAD (6% ± 6%) and jet nebulizer deliver (1% ± 1%) as well. A profile of high pulmonary deposition efficiency and low nasal dose may enable the sustained use of the tPAD platform with a variety of therapeutic agents for a range of pulmonary disorders.