Review
Influence of particle size on regional lung deposition – What evidence is there?

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Abstract

The understanding of deposition of particles in the respiratory tract is of great value to risk assessment of inhalation toxicology and to improve efficiency in drug delivery of inhalation therapies. There are three main basic mechanisms of particle deposition based primarily on particle size: inertial impaction, sedimentation and diffusion. The regional deposition in the lungs can be evaluated in regards to the aerodynamic particle size, in which particle density plays a significant role. In this review paper, we first introduce the available imaging techniques to confirm regional deposition of particles in the human respiratory tract, such as planar scintigraphy, single photon emission computed tomography (SPECT) and positron emission tomography (PET). These technologies have widely advanced and consequently benefited the understanding of deposition pattern, although there is a lack of lung dosimetry techniques to evaluate the deposition of nanoparticles. Subsequently, we present a comprehensive review summarizing the evidence available in the literature that confirms the deposition of smaller particles in the smaller airways as opposed to the larger airways.

Introduction

Particles are deposited in the respiratory tract when they are removed in a definitive fashion from the flow streamline generated by the breathing maneuver. Understanding this process and the factors influencing particles settlement in the surface of specific regions of the airway tree has implications to the development of pharmaceutical inhalation products for aerosol therapy and to risk assessment of air pollutants that concerns toxicology.

Besides pulmonary physiology of patients (e.g. breathing pattern and lung geometry), particle deposition is also known to be influenced by aerosol characteristics (Gonda, 2004, Zeng et al., 2001). Namely, the physicochemical properties of inhaled aerosols that can determine deposition are: size, size distribution, shape, charge, density and hygroscopicity (Pilcer and Amighi, 2010). In the field of aerosol medicine, particle size is a formulation design variable that can be engineered accordingly, aiming the development of pulmonary drug delivery systems (Chow et al., 2007, Shoyele and Cawthome, 2006). As we can examine from the mechanisms of deposition, particle diameter is the primary factor determining pulmonary deposition of aerosols in the various regions of the respiratory tract. Ultimately, inspiratory flow rate also plays an important role in the particle deposition following pulmonary administration (Dolovich, 2000).

In this review paper, we summarize the evidence available in the literature to confirm that smaller particles delivered to the lungs are deposited in the smaller airways as opposed to the larger airways (Fig. 1). So, we first present the mechanisms of particle deposition and the relevance of particle aerodynamic diameter for regional lung deposition. Following, we present experimental techniques that can be used to confirm regional deposition of particles in the respiratory tract. Our focus herein is on evidence of deposition patterns applied to inhalation therapies in humans, based on available data about particle aerodynamic size.

Section snippets

Mechanisms of particle deposition

There are five different mechanisms by which particle deposition can occur in the lungs: inertial impaction, sedimentation, diffusion, interception and electrostatic precipitation. The two latter mechanisms are related, respectively, to particle shape (e.g. elongated particles) and electrostatic charges; and have been reviewed in detail elsewhere (Gonda, 2004, Zeng et al., 2001). The mechanisms of deposition directly (or inversely) related to particle size are presented in Fig. 2.

Particle aerodynamic diameter

Aerosols for inhalation vary not only on geometric particle size and size distribution, but also in a number of other factors that influence particle deposition: physical state (liquid or solid), density, shape and velocity. In addition, a dynamic system of forces is interacting with the airborne particles throughout the airways, namely: gravity, resistant force of the inspiratory air and inertial force. The balance between these forces and the aerosol properties ultimately determines the

Assessment of regional lung deposition

An overview of the commonly used techniques is presented in Fig. 3. There are two basic methods to identify drug deposition in the lungs following inhalation: pharmacokinetic methods and gamma-scintigraphy techniques (Cryan et al., 2007). The former one can only provide information about total lung dose, based on plasma concentrations and/or urinary recovery (Chrystyn, 2001, Koehler et al., 2003). On the other hand, besides quantifying total lung deposition, radionuclide imaging (or

Particle deposition in the lungs

Stahlhofen and coworkers have previously studied the effect of particle size on lung deposition in a systematic experimental design with subjects inhaling monodisperse aerosols during tidal breathing (Stahlhofen et al., 1989). With a tube inserted into the mouth, the oropharyngeal (mouth and throat) deposition for particles greater than 10 μm was more than 90% and 50% at 60 and 18 L/min, respectively. In their study, the smaller airways were differentiated by the larger airways according to the

Establishing clear relationships

The respiratory tract is a complex anatomical structure in which the upper airways gradually decrease in diameter down to the small dimensions of the terminal airways and alveoli. The in vitro determination of aerodynamic diameters has long been explored as a parameter to correlate regional lung deposition with in vivo studies. For the development of inhalation products, the use of cascade impactors highly benefits the fast screening of formulations. Hence, since the studies from Stahlhofen et

Conclusions

Despite the limitations in early imaging techniques used to determine particle deposition in specific zones of the lungs, the technological advances in imaging techniques are gradually improving the capability of differentiating the deposition patterns of particles with increasingly smaller differences in aerodynamic dimensions. With the advances in SPECT and PET, more confirmatory studies are being reported of the evidence of deposition of small particles in the smaller airways, as opposed to

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