Andrew R. Martin

Recent Advances in Predictive Understanding of Respiratory Tract Deposition

Accurate prediction of respiratory tract deposition is important in gauging the health risks of ambient bioaerosols and environmental aerosols, as well as in developing pharmaceutical aerosols for drug delivery. The present article highlights recent advances in the prediction of total, extrathoracic, and lung deposition fractions of inhaled aerosols over a broad range of parameters for both oral and nasal breathing. These advances build on recent data from in vivo and in vitro studies that have benefited from recent improvements in high-resolution imaging, rapid prototyping, and computational simulation abilities that have significantly enhanced the current understanding of respiratory tract deposition. It is anticipated that the relatively simple equations for predicting total or whole lung deposition that follow from the recent work discussed herein will allow for improved correlation between respiratory tract deposition and a wide range of health outcomes.

MRI Measurement of Regional Lung Deposition in Mice Exposed Nose-Only to Nebulized Superparamagnetic Iron Oxide Nanoparticles

Superparamagnetic iron oxide nanoparticles show potential in magnetic targeting of inhaled aerosols to localized sites within the lung. These particles are also used as contrast agents in magnetic resonance imaging (MRI). In the present work, we examine the feasibility of measuring regional lung deposition of iron oxide nanoparticles using MRI. Mice were exposed nose-only to nebulized superparamagnetic iron oxide nanoparticles. The droplet size distribution in the inhalation chamber was measured using a time-of-flight device. Regional concentrations of iron in the left and right lung were assessed with MRI by measuring the longitudinal relaxation times (T(1)) of the lung tissue in exposed mice, compared to a baseline group. Regional concentrations of iron in the lungs of the mice ranged from 1.1 +/- 0.8 microg/cm(3) (mean +/- one standard deviation, n = 6) in peripheral lung regions to 2.7 +/- 1.4 microg/cm(3) in the central lung, with no significant difference between the left and right lung. The nebulized droplets in the inhalation chamber had mass median aerodynamic diameter (MMAD) of 5.6 +/- 0.8 microm, with a geometric standard deviation (GSD) of 1.30 +/- 0.03 (both values expressed as mean +/- one standard deviation, n = 6). MRI shows promise for in vivo measurement of regional lung concentrations of superparamagnetic iron oxide nanoparticles, and may be useful in studies of lung deposition and clearance.

Nebulizers for drug delivery to the lungs

Introduction: Nebulizers are the oldest modern method of delivering aerosols to the lungs for the purpose of respiratory drug delivery. While use of nebulizers remains widespread in the hospital and home setting, certain newer nebulization technologies have enabled more portable use. Varied fundamental processes of droplet formation and breakup are used in modern nebulizers, and these processes impact device performance and suitability for nebulization of various formulations. Areas covered: This review first describes basic aspects of nebulization technologies, including jet nebulizers, various high-frequency vibration techniques, and the use of colliding liquid jets. Nebulizer use in hospital and home settings is discussed next. Complications in aerosol droplet size measurement owing to the changes in nebulized droplet diameters due to evaporation or condensation are discussed, as is nebulization during mechanical ventilation. Expert opinion: While the limelight may often appear to be focused on other delivery devices, such as pressurized metered dose and dry powder inhalers, the ease of formulating many drugs in water and delivering them as aqueous aerosols ensures that nebulizers will remain as a viable and relevant method of respiratory drug delivery. This is particularly true given recent improvements in nebulizer droplet production technology.

The ventilation distribution of helium-oxygen mixtures and the role of inertial losses in the presence of heterogeneous airway obstructions

The regional distribution of inhaled gas within the lung is affected in part by normal variations in airway geometry or by obstructions resulting from disease. In the present work, the effects of heterogeneous airway obstructions on the distribution of air and helium-oxygen were examined using an in vitro model, the two compartments of a dual adult test lung. Breathing helium-oxygen resulted in a consistently more uniform distribution, with the gas volume delivered to a severely obstructed compartment increased by almost 80%. An engineering approach to pipe flow was used to analyze the test lung and was extrapolated to a human lung model to show that the in vitro experimental parameters are relevant to the observed in vivo conditions. The engineering analysis also showed that helium-oxygen can decrease the relative weight of the flow resistance due to obstructions if they are inertial in nature (i.e., density dependent) due to either turbulence or laminar convective losses.

The effect of humidity on the size of particles delivered from metered-dose inhalers

The presence of humidity in air supplied to intubated patients has long been identified as a limiting factor in the delivery of therapeutic aerosols during mechanical ventilation. In this work, the well-known reduction in drug delivery to the lung observed when metered-dose inhalers (MDIs) are actuated into warm, humid airflow was investigated through examination of the evolution of particle size distributions delivered from two commercial hydrofluoroalkane (HFA) MDIs actuated through a standard mechanical ventilation holding chamber. Aerosol deposition in the holding chamber and mass median aerodynamic diameter (MMAD) increased significantly with humidity for both MDIs, regardless of the presence of cosolvent and surfactant in one MDI formulation but not the other. However, in humid air MMAD decreased with distance downstream from the holding chamber, again for both MDIs studied. A modification to the popular assumption of MDI particle growth by condensation is proposed, in which condensed water evaporates back into the supplied airflow subsequent to an initial transient, nucleated condensation. It is anticipated that the present improved understanding of MDI aerosol behavior in humid air may lead to the development of enhanced techniques of drug delivery to mechanically ventilated patients.

Property value estimation for inhaled therapeutic binary gas mixtures: He, Xe, N2O, and N2 with O2

BackgroundThe property values of therapeutic gas mixtures are important in designing devices, defining delivery parameters, and in understanding the therapeutic effects. In the medical related literature the vast majority of articles related to gas mixtures report property values only for the pure substances or estimates based on concentration weighted averages. However, if the molecular size or structures of the component gases are very different a more accurate estimate should be considered.FindingsIn this paper estimates based on kinetic theory are provided of density, viscosity, mean free path, thermal conductivity, specific heat at constant pressure, and diffusivity over a range of concentrations of He-O2, Xe-O2, N2O-O2 and N2-O2 mixtures at room (or normal) and body temperature, 20 and 37°C, respectively and at atmospheric pressure.ConclusionsProperty value estimations have been provided for therapeutic gas mixtures and compared to experimental values obtained from the literature where possible.

Using Helium-Oxygen to Improve Regional Deposition of Inhaled Particles: Mechanical Principles

BACKGROUND Helium-oxygen has been used for decades as a respiratory therapy conjointly with aerosols. It has also been shown under some conditions to be a means to provide more peripheral, deeper, particle deposition for inhalation therapies. Furthermore, we can also consider deposition along parallel paths that are quite different, especially in a heterogeneous pathological lung. It is in this context that it is hypothesized that helium-oxygen can improve regional deposition, leading to more homogeneous deposition by increasing deposition in ventilation-deficient lung regions. METHODS Analytical models of inertial impaction, sedimentation, and diffusion are examined to illustrate the importance of gas property values on deposition distribution through both fluid mechanics- and particle mechanics-based mechanisms. Also considered are in vitro results from a bench model for a heterogeneously obstructed lung. In vivo results from three-dimensional (3D) imaging techniques provide visual examples of changes in particle deposition patterns in asthmatics that are further analyzed using computational fluid dynamics (CFD). RESULTS AND CONCLUSIONS Based on analytical modeling, it is shown that deeper particle deposition is expected when breathing helium-oxygen, as compared with breathing air. A bench model has shown that more homogeneous ventilation distribution is possible breathing helium-oxygen in the presence of heterogeneous obstructions representative of central airway obstructions. 3D imaging of asthmatics has confirmed that aerosol delivery with a helium-oxygen carrier gas results in deeper and more homogeneous deposition distributions. CFD results are consistent with the in vivo imaging and suggest that the mechanics of gas particle interaction are the source of the differences seen in deposition patterns. However, intersubject variability in response to breathing helium-oxygen is expected, and an example of a nonresponder is shown where regional deposition is not significantly changed.

Bridging the Gap Between Science and Clinical Efficacy: Physiology, Imaging, and Modeling of Aerosols in the Lung

Development of a new drug for the treatment of lung disease is a complex and time consuming process involving numerous disciplines of basic and applied sciences. During the 2015 Congress of the International Society for Aerosols in Medicine, a group of experts including aerosol scientists, physiologists, modelers, imagers, and clinicians participated in a workshop aiming at bridging the gap between basic research and clinical efficacy of inhaled drugs. This publication summarizes the current consensus on the topic. It begins with a short description of basic concepts of aerosol transport and a discussion on targeting strategies of inhaled aerosols to the lungs. It is followed by a description of both computational and biological lung models, and the use of imaging techniques to determine aerosol deposition distribution (ADD) in the lung. Finally, the importance of ADD to clinical efficacy is discussed. Several gaps were identified between basic science and clinical efficacy. One gap between scientific research aimed at predicting, controlling, and measuring ADD and the clinical use of inhaled aerosols is the considerable challenge of obtaining, in a single study, accurate information describing the optimal lung regions to be targeted, the effectiveness of targeting determined from ADD, and some measure of the drugs effectiveness. Other identified gaps were the language and methodology barriers that exist among disciplines, along with the significant regulatory hurdles that need to be overcome for novel drugs and/or therapies to reach the marketplace and benefit the patient. Despite these gaps, much progress has been made in recent years to improve clinical efficacy of inhaled drugs. Also, the recent efforts by many funding agencies and industry to support multidisciplinary networks including basic science researchers, R&D scientists, and clinicians will go a long way to further reduce the gap between science and clinical efficacy.

An In Vitro Assessment of Aerosol Delivery Through Patient Breathing Circuits Used with Medical Air or a Helium–Oxygen Mixture

BACKGROUND The bench experiments presented herein were conducted in order to investigate the influence of carrier gas, either medical air or a helium-oxygen mixture (78% He, 22% O2), on the droplet size distribution and aerosol mass delivered from a vibrating mesh nebulizer through a patient breathing circuit. METHODS Droplet size distributions at the exit of the nebulizer T-piece and at the patient end of the breathing circuit were determined by laser diffraction. Additional experiments were performed to determine the effects on measured size distributions of gas humidity and of the droplet residence time during transport from the nebulizer to the laser diffraction measurement volume. Aerosol deposition in the nebulizer, breathing circuit, and on expiratory and patient filters was determined by photometry following nebulization of sodium fluoride solutions into the breathing circuit during simulated patient breathing. RESULTS With no humidification of the carrier gas, droplet volume median diameter (VMD) at the exit of the nebulizer T-piece was 5.5±0.1 μm for medical air, and 4.3±0.1 μm for helium-oxygen. Varying the aerosol residence time between the nebulizer and the measurement volume did not affect the measured size distributions; however, humidification of the carrier gases reduced differences in VMD at the nebulizer exit between medical air and helium-oxygen. At the patient end of the breathing circuit, droplet VMDs were 1.8±0.1 μm for medical air and 2.2±0.1 μm for helium-oxygen. The percentages of sodium fluoride recovered from the nebulizer, breathing circuit, patient filter, and expiratory filter were, respectively, 29.9±8.3, 40.4±5.6, 8.3±1.5, and 21.5±2.1% for air, and 32.6±2.2, 36.3±0.7, 12.0±1.4, and 19.1±1.1% for helium-oxygen. CONCLUSIONS Ventilation with helium-oxygen in place of air-oxygen mixtures can influence both the droplet size distribution and mass of nebulized aerosol delivered through patient breathing circuits. Assessment of these effects on aerosol delivery is important when incorporating helium-oxygen into patient ventilation strategies.

Alignment of Magnetite-Loaded High Aspect Ratio Aerosol Drug Particles with Magnetic Fields

The present note demonstrates magnetic field alignment of high aspect ratio pharmaceutical aerosol particles loaded with magnetite nanoparticles. This alignment is used to reduce the penetration of the particles through polycarbonate membrane filters when a magnetic field is generated parallel to the face of the membrane. Possible application of magnetic field alignment to noninvasively target respiratory tract deposition during aerosol drug delivery is discussed.