Periodic Reporting for period 1 - SprayDelivery (Pulmonary drug delivery using low shear nebulization sprays)
Período documentado: 2024-05-01 hasta 2026-08-31
Respiratory diseases are among the top causes of death worldwide. While many treatments exist, getting the right medicine deep into the lungs effectively remains a major challenge. One of the best ways to treat the lungs is by breathing in a fine mist (aerosols). However, the devices currently used to create these mists are often "too rough". They apply high shear stresses or heat that can break down and damage the medicine before it even reaches the patient. This is a huge problem for modern, delicate medicines like vaccines or lipid-protein drugs, delivered to our lungs.
The overall objective in SprayDelivery project is to develop a new, "gentle" mist technology with a low shear and droplet size control. Think of it as a "soft touch" for medicine. The drug functionality is preserved during the mist generation. By optimizing this delivery strategy, the project enhances targeted deposition in the lungs and significantly reduce medication costs in clinical settings.
The overall objective in SprayDelivery project is to develop a new, "gentle" mist technology with a low shear and droplet size control. Think of it as a "soft touch" for medicine. The drug functionality is preserved during the mist generation. By optimizing this delivery strategy, the project enhances targeted deposition in the lungs and significantly reduce medication costs in clinical settings.
1. Development and validation of low-shear nebulization method: The primary technical focus of this fellowship involved the prototyping and systematic evaluation of a soft aerosolization system specifically engineered for fragile biopharmaceuticals. A central component of this work was a comparative analysis of structural preservation across different nebulization methods, using a commercial pulmonary surfactant as a model. This surfactant—a complex mixture of lipids and proteins secreted by type II alveolar cells—is critical for regulating surface tension at the air–liquid interface of the alveoli and is essential for respiratory function.
While conventional vibrating mesh nebulization was found to disrupt these delicate molecular arrangements, our results demonstrated that the low-shear spray technique maintained the structural integrity of the complex surfactant. Consequently, the biophysical functionality was significantly better preserved, which represents a substantial increase in potential therapeutic effectiveness compared to existing clinical technologies.
2. A simple prediction for drop coalescence: To optimize drug delivery, we investigated the mechanisms of drop coalescence during mist generation. In pulmonary therapy, the deposition site within the airway is dictated by the aerodynamic diameter: droplets between 5–10 μm typically deposit in the central airways, whereas those between 1–5 μm reach the lower respiratory regions. Achieving a narrow droplet size distribution is therefore critical for targeted delivery. However, in many cases, drops tend to coalesce once they approach each other.
We explored how fluid properties, namely viscosity and surface tension, determine drop coalescence regimes. We proposed a novel scaling approach using a dimensionless crossover function that characterizes the smooth transition between viscous and inertial limits. This theoretical framework successfully predicts the regimes and crossover of drop coalescence, providing a robust principle for controlling aerosol characteristics during device operation.
3. Investigations into mucus rheology: The final stage of the project examined the interaction between drug particles and the airway surface, which is covered by a protective, water-based polymeric mucus. This mucus is a viscoelastic fluid with a mesh-like structure that exhibits gel-like properties at the macroscopic level but behaves as a low-viscosity fluid at the microscopic scale.
Using artificial mucus models designed to mimic the rheological profiles of diseased states (such as COPD and asthma), we analyzed the diffusivity of particles within mucus. Our findings revealed that the structural mesh size is a significantly more dominant factor in particle mobility than the macroscopic rheology of the mucus. This discovery provides critical insights for the future design of drug carriers intended to penetrate the mucus barrier in patients.
While conventional vibrating mesh nebulization was found to disrupt these delicate molecular arrangements, our results demonstrated that the low-shear spray technique maintained the structural integrity of the complex surfactant. Consequently, the biophysical functionality was significantly better preserved, which represents a substantial increase in potential therapeutic effectiveness compared to existing clinical technologies.
2. A simple prediction for drop coalescence: To optimize drug delivery, we investigated the mechanisms of drop coalescence during mist generation. In pulmonary therapy, the deposition site within the airway is dictated by the aerodynamic diameter: droplets between 5–10 μm typically deposit in the central airways, whereas those between 1–5 μm reach the lower respiratory regions. Achieving a narrow droplet size distribution is therefore critical for targeted delivery. However, in many cases, drops tend to coalesce once they approach each other.
We explored how fluid properties, namely viscosity and surface tension, determine drop coalescence regimes. We proposed a novel scaling approach using a dimensionless crossover function that characterizes the smooth transition between viscous and inertial limits. This theoretical framework successfully predicts the regimes and crossover of drop coalescence, providing a robust principle for controlling aerosol characteristics during device operation.
3. Investigations into mucus rheology: The final stage of the project examined the interaction between drug particles and the airway surface, which is covered by a protective, water-based polymeric mucus. This mucus is a viscoelastic fluid with a mesh-like structure that exhibits gel-like properties at the macroscopic level but behaves as a low-viscosity fluid at the microscopic scale.
Using artificial mucus models designed to mimic the rheological profiles of diseased states (such as COPD and asthma), we analyzed the diffusivity of particles within mucus. Our findings revealed that the structural mesh size is a significantly more dominant factor in particle mobility than the macroscopic rheology of the mucus. This discovery provides critical insights for the future design of drug carriers intended to penetrate the mucus barrier in patients.
Overview: This project developed and validated an alternative aerosolization strategy for mechanical-stress-sensitive biopharmaceuticals. It also established a simple yet predictive modelling framework for droplet coalescence, which allows to precisely control the aerosol droplet size. Finally, the project demonstrated that mucus mesh size is a critical determinant of drug particle penetration following pulmonary aerosol delivery.
Traditionally, pulmonary aerosol delivery has involved a fundamental trade-off: generating sufficiently fine droplets for deep lung deposition typically requires high mechanical stresses that can degrade sensitive biopharmaceuticals. SprayDelivery has moved beyond this limitation through the implementation of a “soft” nozzle design. It provides clear experimental evidence that complex and fragile therapeutics—such as lung surfactants—can be aerosolized without losing their structural or functional integrity.
A second major outcome of the project is the development of a crossover function to predict droplet coalescence. Previously, droplet coalescence regimes were described by mathematically complex models, limiting their practical use for droplet size control. The project introduces a robust and accessible framework that accounts for fluid viscosity and surface tension in a unified model. This help shed light on the design of next-generation nebulizers with fine droplet size control, ensuring that the mist consistently targets the optimal areas of the respiratory tract.
Finally, the project bridges the gap between mucus rheology and particle transport. While prior studies emphasized particle surface chemistry as the dominant factor governing transport through mucus, our findings reveal that mucus mesh size is a primary determinant of particle penetration. By systematically varying the rheological properties of a model mucus, this project demonstrates that microstructural constraints play a decisive role in particle penetration.
While laboratory models have been successful, the next phase requires in-vivo trials to confirm improved recovery rates and safety. There is a need to work with bodies such as hospitals to establish new standardized protocols for testing drug stability post-aerosolization, ensuring "soft" delivery becomes a recognized safety standard.
Traditionally, pulmonary aerosol delivery has involved a fundamental trade-off: generating sufficiently fine droplets for deep lung deposition typically requires high mechanical stresses that can degrade sensitive biopharmaceuticals. SprayDelivery has moved beyond this limitation through the implementation of a “soft” nozzle design. It provides clear experimental evidence that complex and fragile therapeutics—such as lung surfactants—can be aerosolized without losing their structural or functional integrity.
A second major outcome of the project is the development of a crossover function to predict droplet coalescence. Previously, droplet coalescence regimes were described by mathematically complex models, limiting their practical use for droplet size control. The project introduces a robust and accessible framework that accounts for fluid viscosity and surface tension in a unified model. This help shed light on the design of next-generation nebulizers with fine droplet size control, ensuring that the mist consistently targets the optimal areas of the respiratory tract.
Finally, the project bridges the gap between mucus rheology and particle transport. While prior studies emphasized particle surface chemistry as the dominant factor governing transport through mucus, our findings reveal that mucus mesh size is a primary determinant of particle penetration. By systematically varying the rheological properties of a model mucus, this project demonstrates that microstructural constraints play a decisive role in particle penetration.
While laboratory models have been successful, the next phase requires in-vivo trials to confirm improved recovery rates and safety. There is a need to work with bodies such as hospitals to establish new standardized protocols for testing drug stability post-aerosolization, ensuring "soft" delivery becomes a recognized safety standard.