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The efficacies of inhaled pharmacologic drugs could be improved if drugs could be targeted to appropriate sites within the human respiratory system. The spatial deposition patterns of particles can now be detected with a high degree of resolution using advanced techniques of imaging (e.g., SPECT). However, the effectiveness of such laboratory regimens has been limited by the inability to clearly identify airway composition within images. Therefore, we have developed a theoretical protocol to map airways within human lungs that is designed to be used in a complementary manner with laboratory investigations. The in silico model has two components: a mathematical model based on concepts of topology; and, a computer algorithm which tracks the millions of constituent lung airways. The in silico model produces 3D lung structures that are anatomically correct and can be customized to each patient. We have applied the protocol to a SPECT study where the interiors of lungs were partitioned into a series of ten nested shells. Airway composition in the respective shells provides a heretofore unavailable quantification of scintigraphy images. The protocol can be employed in a practical manner in the medical arena to aid in the interpretation of SPECT images, and to provide a platform for the design of human subject tests., (2006 Wiley-Liss, Inc. and the American Pharmacists Association)

Pollutant particulate matter (PM) is a serious global problem, presenting a threat to the health and well being of human subjects. Inhalation exposures tests with surrogate animals can be performed to estimate the threat. However, it is difficult to extrapolate the findings of animal tests to human conditions. In this two-part series, interspecies dosimetry models especially designed for implementation with risk assessment protocols are presented. In Part I, the mathematical integrity of the source model per se was tested with data from human subjects, and theoretical predictions agreed well with experimental measurements. In Part II, for surrogate (rat) simulations, appropriate algorithms for morphologies and ventilatory parameters were used as subroutines in the validated model. We conducted a comprehensive series of computer simulations describing the behavior of a representative air pollutant, secondary cigarette smoke. For risk assessment interests, a range of states from rest to exercise was considered. PM hygroscopicity had a pronounced effect on deposition in a complex but systematic manner, in humans and rats: deposition was increased for particles larger than about 1 microm, but was decreased for particles smaller than about 0.1 microm. The results clearly indicate that dosimetry models can be effectively used to a priori determine the laboratory conditions necessary for animals tests to accurately mimic human conditions. Moreover, the use of interspecies models is very cost effective. We propose, therefore, that mathematical models be used in a complementary manner with inhalation exposure experiments and be actively integrated into PM risk assessment protocols.

Inhalation toxicology investigations are often performed with laboratory animals to address the potential health effects of inhaled air pollutants on human beings. In Part II of this risk assessment study we have considered the deposition of inhaled particulate matter in the laboratory rat as the surrogate of choice. Calculations were performed in an analogous manner to those conducted in Part I for human subjects. To simulate a wide range of human respiratory intensities associated with different levels of physical activities that must be recognized in the determination of air pollution standards, the CO(2) concentrations within animal inhalation exposure chambers may be controlled. Accordingly, we have regulated rat breathing parameters to correspond to a range of human activities, from rest to work. The results of this interspecies modeling study have been presented in a variety of graphical formats to ease comparisons with findings from experiments and to facilitate integration of the results into risk assessment analyses. The findings of our work clearly demonstrate that interspecies simulations can be employed to design animal tests a priori so that the results can be effectively and efficiently extrapolated to human conditions in a meaningful manner.

Recent findings indicate that the inhalation of large manufactured porous particles may be particularly effective for drug delivery. In this study, a mathematical model was employed to systematically investigate the effects of particle size, particle density, aerosol polydispersity, and patient ventilatory parameters on deposition patterns of inhaled drugs in healthy human lungs. Aerodynamically similar particles with densities of 0.1, 1.0, and 2.0 g/cm(3) were considered. Particle size distributions were defined with mass median aerodynamic diameters (MMADs) ranging from 1 to 3 microm and geometric standard deviations ranging from 1.5 to 2.5, representing particles in the respirable size range. Breathing rates of 30 and 60 L/min with tidal volumes of 500 to 3000 mL were assumed, simulating shallow to deep breaths from a dry powder inhaler. Particles with a high density and a small geometric diameter had slightly greater deposition fractions than particles that were aerodynamically similar, but had lower density and larger geometric size (typical of manufactured porous particles). This can be explained by the fact that particles with a small geometric diameter deposit primarily by diffusion, which is a function of geometric size but is independent of density. As MMAD increased, the effect of density on deposition was less pronounced because of the decreased efficiency of diffusion for large particles. These data suggest that polydisperse aerosols containing a significant proportion of submicron particles will deposit in the pulmonary airways with greater efficiency than aerodynamically similar aerosols comprised of geometrically larger porous particles., (Copyright 2002 Wiley-Liss Inc. and the American Pharmaceutical Association J Pharm Sci 91:1590-1600, 2002)

Knowledge of human lung morphology is a subject critical to many areas of medicine. The visualization of lung structures naturally lends itself to computer graphics modeling due to the large number of airways involved and the complexities of the branching systems. In this study, a method of generating three-dimensional computer simulations of human lung airway networks using data-driven, surface modeling techniques is presented. By simulating the tubular airway structures and realistic bifurcation shapes, anatomically accurate representations of human lungs are obtained. These computer models are designed for use in computational fluid dynamic applications and particle trajectory analyses, and to be complimentary to medical imaging (gamma scintigraphy) protocols.

Knowledge of the structure of the human lung has salient health effects applications. The clinical issues encompass: (1) aerosol therapy, the targeted delivery of inhaled particles to enhance the efficacies of pharmacologic drugs; and (2) nuclear medicine, where planar gamma camera imaging, Single Photon Emission Computer Tomography (SPECT) and Positron Emission Tomography (PET) assess the distribution patterns of radiolabeled diagnostic particles and gases. If the resolution of such images could be enhanced, medical regimens would greatly benefit. Therefore, the focused objective of our work was to develop 3-D mathematical descriptions of the complex airway networks within the lung. A Silicon Graphics workstation was used to depict the daedal structures. The computer-generated color illustrations presented herein are intended to complement medical investigation. They will assist the clinician by serving as templates for the lung and, thereby, providing a real basis for the analysis of relatively abstract images. The illustrations identify individual airways and could be of great importance to physicians in the treatment of airway diseases occurring at well defined locations (e.g. bronchogenic carcinomas). To demonstrate that computers can be actively integrated into medical research and practice we have addressed SPECT images of a subject. Computer templates will aid future clinical investigators in two major ways: (1) the interpretation of a planar gamma camera, SPECT and PET images; and (2) the design of drug testing protocols using inhalation exposures. Considering their usefulness for demonstration, the lung simulations have the potential of playing a substantive role in education.

To accurately assess the potential therapeutic effects of airborne drugs, the deposition sites of inhaled particles must be known. Herein, an original theory is presented for physiologically based pharmacokinetic modeling and related prophylaxis of airway diseases. The mathematical model describes the behavior and fate of particles in the lungs of adult human subjects under various breathing conditions. Their deposition patterns are calculated via superposition of the separate but not independent processes of inertial impaction, sedimentation, and diffusion. The related computer code is designed to calculate total and compartmental (tracheobronchial and pulmonary) distributions of inhaled aerosols. In this manuscript, the model is first tested via comparisons of predicted deposition patterns with laboratory data from human inhalation exposure experiments and then it is applied to determine which factors most influence the dosimetry of inhaled particles. In this format, deposition patterns are explicitly related to particle characteristics, ventilatory parameters, and intersubject variabilities of lung morphologies. The dosimetric model was developed to improve the efficacy of aerosol therapy via the selective deposition of inhaled pharmaceuticals at prescribed lung locations to elicit optimum effects.