Aerosol Drug Delivery Research Articles

High-precision ultrasonic atomization using oscillating microchannels: Interplay of three-dimensional vibrational modes and droplet ejection mechanisms

Ultrasonic atomization is a critical process for producing micrometer-diameter droplets, widely utilized in aerosol drug delivery, spectrometry, and printing. The geometry of the vessel containing the fluid being atomized and the oscillations of its sidewalls play a crucial role in controlling the wave patterns and hence the droplet ejection process, especially at actuation frequencies exceeding 1 MHz. However, the mechanisms behind droplet ejection under high-frequency ultrasonic actuation remain poorly understood. We employ oscillating high-aspect-ratio Silicon microchannels to create ideal conditions where capillary forces, microchannel geometry, and oscillatory motion work together to precisely confine a liquid film and generate droplets with controlled diameters. We show that the three-dimensional vibrations of the microchannels, particularly the interplay between actuation frequency, amplitude, and channel geometry, can be used to effectively tune the ligament development and droplet breakup. This understanding allows us to establish conditions to reduce actuation power and hence minimize heating, control shear stresses and tune the droplet size on-demand without compromising uniformity and throughput.

The effect of decoupling humidity control on aerosol drug delivery during HFNC for infants.

Aerosol therapy is commonly used during treatment with high-flow nasal cannula (HFNC) in the intensive care unit (ICU). Heated humidification inside the HFNC tubing circuit leads to unwanted condensation, which may greatly limit the efficiency of drug delivery. In this study, we aimed to investigate whether a novel humidification system, which decouples temperature and humidity control, can improve the delivered dose. In a bench study setup, fluorescein sodium solution was nebulized using a vibrating-mesh nebulizer in an infant HFNC circuit to measure the delivered dose, with a conventional versus a novel decoupled humidifier. The deposition of fluorescein inside each breathing circuit component and a final collection filter at the end of the nasal cannula was collected and quantified with a UV-vis spectrometer. Droplet sizes at different sections of the breathing circuit were measured by laser diffraction. Three air flow rates: 5, 10 and 15 L/min, and two nebulizer positions: (1) at the humidifier and (2) after the inspiratory tube, were tested. The delivered dose decreased with increasing flow rate for the conventional setup and was higher when the nebulizer was placed after the inspiratory tube. Turning off the conventional humidifier 10 minutes before and during nebulization did not improve the delivered dose. The decoupled humidifier achieved a significantly higher (p = .002) delivered dose than the conventional setup. The highest delivered dose obtained by the decoupled humidifier was 62.4% when the nebulizer was placed after the humidifier, while the highest dose obtained for the conventional humidifier was 36.3% by placing the nebulizer after the inspiratory tube. In this bench study, we found that the delivered dose for an infant HFNC nebulization setup could be improved significantly by decoupling temperature and humidity control inside the HFNC circuit, as it reduced drug deposition inside the breathing circuit.

Effect of airway wall motion on particle deposition and delivery in the neonatal trachea

Modeling pulmonary drug delivery in the airway using computational fluid dynamics (CFD) simulations tracks drug particles throughout the airway, providing valuable information on the deposition location of inhaled drugs. However, most studies simulate particle transport within static airway models that do not incorporate physiological airway motion; this choice limits accuracy since airway motion directly affects particle transport and deposition, notably in newborns with airway abnormalities such as tracheomalacia. The objective of this study is to determine the effect of airway motion on drug delivery in neonates with and without airway disease. For this study, two control subjects without any airway disease and three subjects with tracheomalacia (dynamic tracheal narrowing) were enrolled. Each subject was imaged at approximately 40-weeks post-menstrual age using magnetic resonance imaging (MRI). MRI data were retrospectively reconstructed to obtain static airway images gated to different time points of the breath (i.e., end expiration and end inspiration) and an image representing combined data from all timepoints (ungated). Virtual airway surfaces (pharynx to main bronchi) were made from each MR image. A moving airway surface was created from surface registration of these surfaces and used as the boundary for a CFD simulation of one inhalation, along with subject-specific inspiratory flow waveforms. To assess the effect of airway wall motion on particle deposition, static-walled simulations, based on the airway surfaces at end inspiration, end expiration, and the ungated airway surface, were also performed using the same flow boundary conditions. Particle transport (particles diameter range 0.5–15 μm) was compared between the simulations during the inhalation. Airway surface motion affected particle transport into the small airways by 65% on average (0.5–5 μm– 22%, 5-15 μm– 86%) compared to static-walled simulations, while comparison between static end expiration and other static-walled simulations using geometries acquired during different phases of breathing differed by more than 500% on average (0.5–5 μm– 45%, 5-15 μm– 741%). For particle deposition, airway surface motion affected by 43% on average (0.5–5 μm– 86%, 5-15 μm– 21%) compared to static-walled simulations and comparison between static end expiration and other static-walled simulations differed by 47% on average (0.5–5 μm– 58%, 5-15 μm– 41%). Differences between dynamic and static deposition results and between static simulations from different timepoints occurred in patients with and without airway disease. This study suggests the importance of using airway wall motion in CFD simulations to model aerosolized drug delivery in the airway. If a CFD simulation is limited to only a static airway image without physiological motion, particle deposition mapping may yield markedly inaccurate results, potentially resulting in higher or lower drug dosing than intended.

Changes in Peak Inspiratory Flow After Acute Bronchodilation: An Observational Study of Patients with Stable Chronic Obstructive Pulmonary Disease.

Introduction: Identifying factors influencing peak inspiratory flow (PIF) is essential for aerosol drug delivery in stable patients with chronic obstructive pulmonary disease. While a minimum PIF for dry powder inhalers (DPIs) is established, acute bronchodilator (BD) effects on PIF remain unknown. Materials and Methods: An inspiratory flow meter (In-Check™ DIAL) was used to measure PIF in stable patients during a 24-week observational cross-sectional study. Additionally, bronchodilator responsiveness (BDR) was determined using the In-Check DIAL device and spirometry. Patients received four puffs of albuterol, and pre- and post-BD PIF, forced expiratory volume in one second (FEV1), and forced vital capacity were measured. Sixty-three patients completed acute BDR data collection from July 31, 2019, to November 9, 2021. Primary endpoints were pre- and post-BD spirometry and PIF. Statistical analyses included PIF correlations with FEV1. BD change was assessed according to inhaler resistance and sex (subgroup analysis). Results: Median patient age was 64.8 years, 85.7% were non-Hispanic White, and 57.1% were female. The median increase in absolute PIF (In-Check DIAL) was 5.0 L/min, and the % PIF change was 8.9%. With albuterol, 57.1% experienced a PIF BD change >5.0%, whereas 49.2% experienced a change >10.0%. Similarly, 55.6% experienced an FEV1 BD change >5.0% and 28.6% had a >10.0% FEV1 BD change with albuterol. PIF was weakly correlated with FEV1 BD change (absolute; % PIF; r = 0.28 [p = 0.02]; r = 0.21 [p = 0.11]). Pre- and post-BD median PIF were 75.5 and 83.5 L/min for low-to-medium-resistance DPI and 45.0 and 52.0 L/min for high-resistance, respectively. The median increases in pre- and post-BD PIF were 9.0 L/min in males and 4.5 L/min in females. In contrast to when using the In-Check DIAL device, we observed no consistent bronchodilatory effects on PIF measured by spirometry. Conclusions: Using the In-Check DIAL device, ∼50% of patients experienced >10% PIF increase after acute BD, potentially enhancing medication lung deposition. Further research is required to understand PIF's impact on medication delivery. ClinicalTrials.gov Identifier: NCT04168775.

High-flow nasal cannula and in-line aerosolised bronchodilator delivery during severe exacerbation of asthma in adults: a feasibility observational study

BackgroundAsthma is a common chronic respiratory disease affecting 1–29% of the population in different countries. Exacerbations represent a change in symptoms and lung function from the patient's usual condition that requires emergency department (ED) admission. Recently, the use of a High-Flow Nasal Cannula (HFNC) plus an in-line vibrating mesh nebulizer (VMN) for aerosol drug delivery has been advocated in clinical practice. Thus, this pilot observational study aims to investigate the feasibility of HFNC treatment with VMN for in-line bronchodilator delivery in patients with severe asthma. MethodsThis study was conducted from May 2022 to May 2023. Subjects ≥18 years old with a previous diagnosis of asthma who were admitted to the ED during severe exacerbation were included. The primary endpoint was the change in peak expiratory flow ratio (PEFR) after 2-h of treatment with bronchodilator delivered by HFNC with in-line VMN. Additional outcomes were changes in forced expiratory volume in 1 s (FEV1) and clinical variables before treatment. Results30 patients, mean age of 43 (SD ± 16) years, mostly female (67%) were studied. A significant change in PEFR (147 ± 31 L/m vs. 220 ± 38 L/m; p < 0.001) was observed after treatment with HFNC and in-line VMN with significant improvement in clinical variables. And no subjects required invasive mechanical ventilation (IMV) during the study. ConclusionsHFNC treatment with in-line VMN for bronchodilator delivery appears feasible and safe for patients with severe asthma exacerbation. These preliminary promising results should be confirmed with appropriately large-designed studies.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC): Why it will Transform Cancer Surgery

Abstract Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) represents an innovative method for delivering chemotherapy directly into the abdominal cavity, offering a targeted, effective, and less toxic treatment option for patients with non-resectable peritoneal metastasis (PM). PIPAC is increasingly adopted due to its benefits over traditional therapies, including enhanced drug penetration, reduced systemic toxicity, and improved efficacy in chemoresistant PM. Performed laparoscopically, PIPAC is minimally invasive, often outpatient, and well-tolerated, preserving patients' quality of life. So far, PIPAC has been mainly used in advanced PM from ovarian, gastric, and colorectal cancers, where it can be effective even after other treatments have failed. The repeatable nature of PIPAC offers opportunities for maintenance therapy and long-term disease control. A recent meta-analysis of PIPAC studies reported a 4% non-access rate and 39% of patients completing three or more cycles, with only 4% experiencing severe toxicities. Pathological responses were observed in 68% of cases, indicating reliable efficacy. A first randomized trial showed PIPAC’s superiority in objective response rates and quality of life compared to intravenous chemotherapy for platinum-resistant ovarian cancer. Research in PIPAC is dynamic and multidisciplinary, aiming to refine the technique, minimize side effects, and expand its applicability to various cancers. Studies focus on the efficacy of aerosolized drug delivery, including nanoparticles and RNA-based therapies, which offer targeted treatment options with promising therapeutic potential. Innovations such as electrostatic precipitation PIPAC (ePIPAC) combine enhanced drug distribution with increased tissue penetration, representing significant advancements in PM treatment. Future developments will focus on optimizing aerosol characteristics, drug formulations, and personalized medicine approaches.

Inhaled aerosolized algal polysaccharides: A novel and reliable strategy for treating pneumonia through inflammation and oxidative stress inhibition

Sepsis-associated acute lung injury (ALI) poses a significant threat, characterized by inflammation and oxidative damage. Effective drugs targeting these aspects with reliable drug delivery systems are vital for ALI management. This study aimed to evaluate the influence of algal polysaccharides (APs) with aerosolized drug delivery in ALI mice and clarify the underlying mechanism. To induce the sepsis-associated acute lung injury (ALI) model, mice were administered intraperitoneal injections of 10 mg/kg LPS for 48 h in vivo. ALI mice received APs via atomization to arrive at different sites within the lungs. Lung tissue samples and bronchoalveolar lavage fluid (BALF) were collected to access lung injury parameters. Concurrently, western blotting, H&E staining, and immunofluorescence (IF) were applied to investigate the specific impact of APs on ALI. The results showed that APs protect lung tissue against ALI by inhibiting inflammation and mitigating oxidative stress-induced damage. This study highlights promising avenues for ALI intervention using natural compounds with anti-inflammatory and antioxidant properties.

Effects of the deformation and size of the upper airway on the deposition of aerosols

Aerosol drug delivery in the human airway is significantly affected by the morphology and size of the airway. This work developed a CFD-DEM model to simulate and analyze air flow and powder dynamics in combined inhaler-airway systems with different degrees of airway deformation (non-deformed, 50%, and 75% deformed) and sizes (adult, 0.80, and 0.62 scaled). The airways were generated based on a regular airway constructed from the MRI images through finite element method (for deformed airways) or scaling-down (for smaller airways). The airways were connected to Turbuhaler® through a connector. The results showed that under the same flow rate, the variation in the airway geometry and size had a minimum impact on the flow field and powder deposition in the device and the connector. However, deformation caused more particle deposition in the deformed region. Notably, the airway with 50% deformation had the most particles passing through the airway with the largest particle sizes due to its lower air velocity in the deformed area. Reducing airway size resulted in more powder deposition on the airway, particularly at the pharynx and mouth regions. This was because, with the same flow rate, the flow velocity in the smaller airway was higher, causing more particle–wall collisions in the mouth and pharynx regions. More importantly, the deposition efficiency in the 0.62-scaled airway was significantly higher than the other two airways, highlighting the importance of the different administration of aerosol drugs for young children.

The Effects of Inspiratory Flows, Inspiratory Pause, and Suction Catheter on Aerosol Drug Delivery with Vibrating Mesh Nebulizers During Mechanical Ventilation.

Background: Some experts recommend specific ventilator settings during nebulization for mechanically ventilated patients, such as inspiratory pause, high inspiratory to expiratory ratio, and so on. However, it is unclear whether those settings improve aerosol delivery. Thus, we aimed to evaluate the impact of ventilator settings on aerosol delivery during mechanical ventilation (MV). Methods: Salbutamol (5.0 mg/2.5 mL) was nebulized by a vibrating mesh nebulizer (VMN) in an adult MV model. VMN was placed at the inlet of humidifier and 15 cm away from the Y-piece of the inspiratory limb. Eight scenarios with different ventilator settings were compared with endotracheal tube (ETT) connecting 15 cm from the Y-piece, including tidal volumes of 6-8 mL/kg, respiratory rates of 12-20 breaths/min, inspiratory time of 1.0-2.5 seconds, inspiratory pause of 0-0.3 seconds, and bias flow of 3.5 L/min. In-line suction catheter was utilized in two scenarios. Delivered drug distal to the ETT was collected by a filter, and drug was assayed by an ultraviolet spectrophotometry (276 nm). Results: Compared to the use of inspiratory pause, the inhaled dose without inspiratory pause was either higher or similar across all ventilation settings. Inhaled dose was negatively correlated with inspiratory flow with VMN placed at 15 cm away from the Y-piece (rs = -0.68, p < 0.001) and at the inlet of humidifier (rs = -0.83, p < 0.001). The utilization of in-line suction catheter reduced inhaled dose, regardless of the ventilator settings and nebulizer placements. Conclusions: When VMN was placed at the inlet of humidifier, directly connecting the Y-piece to ETT without a suction catheter improved aerosol delivery. In this configuration, the inhaled dose increased as the inspiratory flow decreased, inspiratory pause had either no or a negative impact on aerosol delivery. The inhaled dose was greater with VMN placed at the inlet of humidifier than 15 cm away the Y-piece.

Abstract 491: Aerosol delivery of immunotherapy and hesperetin nanoparticles in murine lung cancer model

Abstract Purpose: Radiation is the most common modality for lung cancer treatment method. Radiationinduces apoptosis, causing cancer cells to be fragmented and expose the cancer-associatedantigens to the tumor microenvironment. These can be recognized by antigen-presenting cells(APC) to induce the antineoplastic effect by activating cytotoxic T cells. Our prior studies showadding immunoadjuvant like AntiCD40 with radiation can further activate the APCs in its anti-tumor (M1) format. Recent studies have shown that flavonoids like Hesperetin, an ACE2receptor agonist also can induce apoptosis in cancer cells whereas ACE2 receptors are abundant in lung cancer cells.This project aims to develop a novel treatment for non-small cell lung cancer (NSCLC) using nanotechnology for inhalation drug delivery Hesperetin, a flavonoid with antioxidant and pro-apoptotic activity; bound to PLGA-coated nanoparticles (Hesperetin Nanoparticles, HNPs) andAntiCD40 aiming for localized targeted dosing to reduce the treatment-related systemic toxicity.We plan to test the efficacy and safety of this aerosol spray. Methods: In-vitro studies were performed in human A549 (ATCC) and murine LLC1 (ATCC)lung cancer cell lines for growth (MTT) and clonogenic survival assays to demonstrate the anti-cancer cell activity of Hesperetin (Sigma). Next, HNP was prepared using NanoFabTx™ nano-formulation reagent kits (Millipore-Sigma). A syngeneic orthotopic murine model of Lungadenoma was generated in wild (+/+) C57/BL6 background mice with similar background LLC1cell lines. We developed syngeneic orthotopic murine lung tumors with luciferase genetransfected LL/2-Luc2 (ATCC) Lewis Lung Cancer cell line in wild-type C57BL/6 mice(Techonic). Lung tumor-bearing mice were treated with HNP, antiCD40, or both with aerosolspray with a control group treated with the solvent (dH2O) only. To assess the drug delivery withaerosol treatment ex-vivo lung tissue was analyzed for Fluorescence tagged antiCD40 andnanoparticle uptakes. A survival assay was performed to analyze the efficacy of aerosoltreatment of HNPs with or without AntiCD40. All cohorts were also analyzed for body score, body weight, and liver and kidney functions. Results: We were able to successfully develop an aerosol drug delivery model to administer bothAnti-CD40 and HNP in a murine lung cancer model. In our analysis of an orthotopic murinelung cancer model, we demonstrate a high intake of the HNP and AntiCD40 by the cancer cellssparing the normal lung tissue. Moreover, the highest percentage of survival rate was observed with the combination aerosol treatment with HNP+AntiCD40 (p&amp;lt;0.001), compared to CD40alone (p&amp;lt;0.01) or HNP (p&amp;lt;0.01) alone. Comments: This treatment model will allow us to make the lung cancer treatment method easilyavailable for the mass population without having hazardous radiation treatment in the lungcancer model. Citation Format: Sayeda Yasmin-Karim, Geraud Richard, Amanda Fam, Alina-Marissa Ogurek, G. Mike Makrigiorgos. Aerosol delivery of immunotherapy and hesperetin nanoparticles in murine lung cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 491.

Advances in Aerosol Formulation for Targeted Delivery of Therapeutic Agents from Nose to Brain.

The intricate anatomical and physiological barriers that prohibit pharmaceuticals from entering the brain continue to provide a noteworthy hurdle to the efficient distribution of medications to brain tissues. These barriers prevent the movement of active therapeutic agents into the brain. The present manuscript aims to describe the various aspects of brain-targeted drug delivery through the nasal route. The primary transport mechanism for drug absorption from the nose to the brain is the paracellular/extracellular mechanism, which allows for rapid drug transfer. The transcellular/intracellular pathway involves the transfer across a lipoidal channel, which regulates the entry or exit of anions, organic cations, and peptides. Spectroscopy and PET (positron emission tomography) are two common methods used for assessing drug distribution. MRI (Magnetic resonance imaging) is another imaging method used to assess the efficacy of aerosol drug delivery from nose to brain. It can identify emphysema, drug-induced harm, mucus discharge, oedema, and vascular remodeling. The olfactory epithelium's position in the nasal cavity makes it difficult for drugs to reach the desired target. Bi-directional aerosol systems and tools like the "OptiNose" can help decrease extranasal particle deposition and increase particle deposition efficiency in the primary nasal pathway. Direct medicine administration from N-T-B, however, can reduce the dose administered and make it easier to attain an effective concentration at the site of activity, and it has the potential to be commercialized.

Hyperthermic pressurized intraperitoneal aerosol drug delivery system in a large animal model: a feasibility and safety study.

We developed a novel drug delivery system called hyperthermic pressurized intraperitoneal aerosol chemotherapy (HPIPAC) that hybridized Hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). The present study aims to assess the feasibility and safety of HPIPAC system in a large animal survival model. Eleven pigs (eight non-survival models and three survival models) were used in the experiment. The heat module in the HPIPAC controller circulates hyperthermic CO2 in a closed-loop circuit and creates gas-based dry intraperitoneal hyperthermia. Three 12mm trocars were placed on the abdomen. The afferent CO2 tube wound with heat generating coil was inserted into a trocar, and the efferent tube was inserted into another trocar. Heated CO2 was insufflated and circulated in a closed circuit until the intra-abdominal and peritoneal surface temperature reached 42°C. 100ml of 5% dextrose in water was nebulized for 5min and the closed-loop circulation was resumed for 60min at 42°C. Tissue biopsies were taken from several sites from the pigs in the survival model. The average change in core temperature of the pigs was 2.5 ± 0.08°C. All three pigs displayed no signs of distress, and their vital signs remained stable, with no changes in their diet. In autopsy, inflammatory and fibrotic responses at the biopsy sites were observed without serious pathologic findings. We successfully proved the feasibility and safety of our novel HPIPAC system in an in-vivo swine survival model.

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.

Enhancing Inhalation Drug Delivery: A Comparative Study and Design Optimization of a Novel Valved Holding Chamber.

This paper presents an innovative approach to the design optimization of valved holding chambers (VHCs), crucial devices for aerosol drug delivery. We present the design of an optimal cylindrical VHC body and introduce a novel valve based on particle impaction theory. The research combines computational simulations and physical experiments to assess the performance of various VHCs, with a special focus on the deposition patterns of medication particles within these devices. The methodology incorporates both experimental and simulation approaches to validate the reliability of the simulation. Emphasis is placed on the deposition patterns observed on the VHC walls and the classification of fine and large particles for salbutamol sulfate particles. The study reveals the superior efficacy of our valve design in separating particles compared to commercially available VHCs. In standard conditions, our valve design allows over 95% of particles under 7 μm to pass through while effectively filtering those larger than 8 μm. The optimized body design accomplishes a 60% particle mass flow fraction at the outlet and an average particle size reduction of 58.5%. When compared numerically in terms of size reduction, the optimal design outperforms the two commercially available VHCs selected. This study provides valuable insights into the optimization of VHC design, offering significant potential for improved aerosol drug delivery. Our findings demonstrate a new path forward for future studies, aiming to further optimize the design and performance of VHCs for enhanced pulmonary drug delivery.

The potential of leveraging electrostatics for improved inhaled drug delivery to the lungs

In this short perspective, we explore the potential of leveraging electrostatic forces in the lungs to enhance pulmonary drug delivery methods and optimize drug delivery efficiency and therapeutic outcomes. Alongside conventional mechanisms such as diffusion, gravitational sedimentation, and impaction, we delve into electrostatic mechanisms, utilizing a non-dimensional analysis approach for insights into aerosol drug delivery. While often overlooked in inhalation therapy, our considerations emphasize the significance of electrostatic interactions on drug deposition, particularly in the deep lung, where, in the future, tailored electrostatic charges can strategically offer new possibilities for localized therapeutic effects for respiratory diseases.

Entrapment of Ibuprofen by Multilamellar Liposomes for Aerosol Drug Delivery Towards Sustained Release Upon Pulmonary Administration

Entrapment of Ibuprofen by Multilamellar Liposomes for Aerosol Drug Delivery Towards Sustained Release Upon Pulmonary Administration

Enhanced Aerosol Delivery During High-Flow Nasal Cannula Therapy.

Aerosolized drug delivery via high-flow nasal cannula (HFNC) decreases as gas flow is increased. To improve aerosol delivery, breath-enhanced jet nebulizer may increase aerosol output. This study tested that hypothesis and compared breath-enhanced jet nebulizer to vibrating mesh nebulizer technology. First, in an isolated circuit, breath-enhanced jet nebulizer and vibrating mesh nebulizer aerosol outputs were measured during simulated HFNC by using infused saline solution at rates of 5-60 mL/h. Limits were defined when nebulizer filling was detected. The devices were then tested by using 99mTc/saline solution to measure maximum rates of aerosol production. After the output experiments, drug delivery was measured in vitro by using a model that consisted of an HFNC circuit interfaced to a realistic 3-dimensional printed head. The 99mTc/saline solution was infused at rates of 5 to 60 mL/h for the breath-enhanced jet nebulizer and 5 to 20 mL/h for the vibrating mesh nebulizer with HFNC gas flows of 10 to 60 L/min. Aerosol delivery to the trachea was measured by using a shielded ratemeter, which defined the rate of drug delivery (µg NaCl/min). With increasing gas flow, breath-enhanced jet nebulizer output increased to a maximum of 50 mL/h, the vibrating mesh nebulizer maximum was 12 mL/h. At HFNC gas flow of 60 L/min, breath-enhanced jet nebulizer delivered 3.16 to 316.8 µg NaCl/min, the vibrating mesh nebulizer delivered 23.5 to 61.7 µg NaCl/min. For infusion pump flows of 5 to 12 mL/h, the rate of drug delivery was independent of nebulizer type (P = .19) and dependent on infusion pump flow (P < .001) and gas flow (P < .001). Increasing gas flow increased breath-enhanced jet nebulizer output, which demonstrated the effects of breath enhancement. At 60 L/min, breath enhanced jet nebulizer delivered up to 5 times more aerosol compared with conventional vibrating mesh nebulizer technology. Breath-enhanced jet nebulizer delivered a wide range of dose rates at all high flows. In patients who are critically ill, breath-enhanced jet nebulizer technology may allow titration of bedside dosing based on clinical response by simple adjustment of the infusion rate.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 33.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 33.

Universal scaling of droplet retraction dynamics on vibrating surfaces

Over the past decade, extensive efforts have been made in the study of droplet impact, especially on stationary surfaces, owing to its direct applications in thermal cooling, self-cleaning, and power generation. However, many practical applications, such as ultrasonic cleaning, aerosolized drug delivery, and vibration-assisted welding, involve the direct interaction of droplets with vibrating surfaces, on which droplets undergo spreading and retraction. Distinct from stationary surfaces where the retraction behaviors, such as the retraction velocity and rate, are mainly governed by the surface wettability and droplet inertia, the retraction behaviors on vibrating surfaces become complicated due to the vibration velocity, which dictates the outcomes of droplet impact, such as the pinning, bouncing, gyrating, and jetting. Here, we revealed the synergistic effect of droplet inertia and vibration velocity on droplet retraction. We found that the droplet retraction behaviors on both stationary and vibrating surfaces could be characterized by a universal scaling law, allowing us to analyze and predict the maximum droplet retraction velocities. Moreover, we found that the maximum retraction rate increased with the maximum spreading radius at low Weber numbers. We demonstrated that the droplet retraction dynamics at both low Weber numbers and high Weber numbers could be unified into one integrated model, which indicates the decisive role of the maximum droplet spreading in droplet retraction dynamics.

Scaling toward Diminutive MEMS: Dust‐Sized Spray Chips for Aerosolized Drug Delivery to the Lung

AbstractThe functional area of silicon‐based microelectromechanical systems (MEMS) devices often occupies only a fraction of the actual silicon area of the chip. As the chip cost directly scales with the total chip area, there is an incentive to reduce the chip to the smallest possible size. However, handling such diminutive devices poses challenges that industry‐standard packaging cannot solve. Here, the world's smallest spray nozzle chip for drug delivery to the lung is manufactured and packaged and how magnetic assembly combined with microfluidic glue fixation can overcome this barrier for diminutive MEMS devices is demonstrated. The spray nozzle chips have a circular footprint with a diameter of 280 µm and feature a nickel coating on their conical sidewall, allowing magnetic manipulation. The chips are assembled and sealed into plastic substrates using a three‐step gluing process guided by capillary action and activated by heat. Assembly speeds of up to 147 chips per minute are demonstrated and fabrication to packaging and functional operation of this device is shown for the target application.