The success of inhalation therapy is not only dependent upon the pharmacology of the drugs being inhaled but also upon the site and extent of deposition in the respiratory tract. This article reviews the main mechanisms affecting the transport and deposition of inhaled aerosol in the human lung. Aerosol deposition in both the healthy and diseased lung is described mainly based on the results of human studies using nonimaging techniques. This is followed by a discussion of the effect of flow regime on aerosol deposition. Finally, the link between therapeutic effects of inhaled drugs and their deposition pattern is briefly addressed. Data show that total lung deposition is a poor predictor of clinical outcome, and that regional deposition needs to be assessed to predict therapeutic effectiveness. Indeed, spatial distribution of deposited particles and, as a consequence, drug efficiency is strongly affected by particle size. Large particles (>6 μm) tend to mainly deposit in the upper airway, limiting the amount of drugs that can be delivered to the lung. Small particles (<2 μm) deposit mainly in the alveolar region and are probably the most apt to act systemically, whereas the particle in the size range 2–6 μm are be best suited to treat the central and small airways.

The success of inhalation therapy is not only dependent upon the pharmacology of the drugs being inhaled but also upon the site and extent of deposition in the respiratory tract. Similarly, the toxicity of environmental and industrial particulate matter is affected not only by the nature of the dust but also by the amount and spatial distribution of deposited particles in the lung. Aerosol deposition is primarily governed by the mechanisms of inertial impaction, gravitational sedimentation, Brownian diffusion, and, to a lesser extent, by turbulence, electrostatic precipitation, and interception. The relative contribution of these different mechanisms is a function of the physical characteristics of the particles, the lung structure, and the flow patterns. Large particles (>5 μm) tend to deposit mainly in the upper and large airways, limiting the amount of aerosols that can be delivered to the lung. Small particles (<2 μm) deposit mainly in the alveolar region, whereas particles in the size range 2–5 μm deposit preferentially in the central and small airways.

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 drug's 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.

Although the major mechanisms of aerosol deposition in the lung are known, detailed quantitative data in anatomically realistic models are still lacking, especially in the acinar airways. In this study, an algorithm was developed to build multigenerational three-dimensional models of alveolated airways with arbitrary bifurcation angles and spherical alveolar shape. Using computational fluid dynamics, the deposition of 1- and 3-μm aerosol particles was predicted in models of human alveolar sac and terminal acinar bifurcation under rhythmic wall motion for two breathing conditions (functional residual capacity = 3 liter, tidal volume = 0.5 and 0.9 liter, breathing period = 4 s). Particles entering the model during one inspiration period were tracked for multiple breathing cycles until all particles deposited or escaped from the model. Flow recirculation inside alveoli occurred only during transition between inspiration and expiration and accounted for no more than 1% of the whole cycle. Weak flow irreversibility and convective transport were observed in both models. The average deposition efficiency was similar for both breathing conditions and for both models. Under normal gravity, total deposition was ∼33 and 75%, of which ∼67 and 96% occurred during the first cycle, for 1- and 3-μm particles, respectively. Under zero gravity, total deposition was ∼2–5% for both particle sizes. These results support previous findings that gravitational sedimentation is the dominant deposition mechanism for micrometer-sized aerosols in acinar airways. The results also showed that moving walls and multiple breathing cycles are needed for accurate estimation of aerosol deposition in acinar airways.

Darquenne, Chantal, Manuel Paiva, John B. West, and G. Kim Prisk. Effect of microgravity and hypergravity on deposition of 0.5- to 3-μm-diameter aerosol in the human lung. J. Appl. Physiol. 83(6): 2029–2036, 1997.—We measured intrapulmonary deposition of 0.5-, 1-, 2-, and 3-μm-diameter particles in four subjects on the ground (1 G) and during parabolic flights both in microgravity (μG) and at ∼1.6 G. Subjects breathed aerosols at a constant flow rate (0.4 l/s) and tidal volume (0.75 liter). At 1 G and ∼1.6 G, deposition increased with increasing particle size. In μG, differences in deposition as a function of particle size were almost abolished. Deposition was a nearly linear function of the G level for 2- and 3-μm-diameter particles, whereas for 0.5- and 1.0-μm-diameter particles, deposition increased less between μG and 1 G than between 1 G and ∼1.6 G. Comparison with numerical predictions showed good agreement for 1-, 2-, and 3-μm-diameter particles at 1 and ∼1.6 G, whereas the model consistently underestimated deposition in μG. The higher deposition observed in μG compared with model predictions might be explained by a larger deposition by diffusion because of a higher alveolar concentration of aerosol in μG and to the nonreversibility of the flow, causing additional mixing of the aerosols.