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Validated Three Dimensional CFD Modelling of Aerosol Drug Deposition in Humans - Influence of Disease and Breathing Regimens

Apiou-Shirlea G, Simoes-Pichelin M, Caillibotte G, Katz I, Texereau J, Fleming JS, Conway JH, Scheuch G, Martonen TB.

Respiratory Drug Delivery 2008. Volume 1, 2008: 185-196.

Abstract:

Mathematical modeling and computer simulations have been integrated with human subject experiments to provide a sound scientific basis for drug delivery customized to patients’ anatomy, physiology and pathology. Our hypothesis is that by targeting inhaled pharmaceuticals to appropriate deposition sites the efficacies of drugs may be enhanced. Deposition patterns of aerosolized particles have been generated mathematically based upon the interaction between four families of variables describing: (i) morphology, (ii) respiration, (iii) fluid motion, and (iv) aerosol characteristics. The extrathoracic (ET) and upper tracheobronchial (TB) tree (generations 0 to 6 where 0 represents the trachea) components of the morphology have been determined by high resolution computed tomography (HRCT). The lower TB tree (generations 7 to 16) and pulmonary (P) components of the morphology have been generated by using morphometric data to reproduce the complex airway branching network into the lungs. The resultant in silico model integrates both morphology components. Three dimensional (3D) Computational Fluid Dynamic (CFD) and deterministic techniques have been coupled to characterize the gas flow and integrated with the in silico model. Particle deposition patterns have been calculated as a function of aerosol characteristics. In addition, effects of different gas mixtures (i.e., helium + oxygen = Oxhel) as carriers for the aerosolized drugs have been addressed. Good agreement has been observed when results of the deterministic analyses were compared with regional in vivo human subject data, and when results of the 3D CFD analyses were compared with in vitro particle deposition data from human casts, thereby validating the use of such modeling techniques in healthy male adults. Results from preliminary single photon emission computed tomography (SPECT) studies conducted at Southampton General Hospital for healthy and asthmatic subjects have shown qualitative agreement between deterministic calculated data and experimental observations for coarse mode aerosols and controlled tidal breathing regimes. By expressing particle deposition in terms of inhaler parameters (e.g., particle sizes and concentrations, carrier gas mixture) and patient characteristics (e.g., airway morphologies and breathing conditions), modeling can lead to the design and development of improved inhalers and be employed to target the delivery of aerosolized drugs to elicit optimum therapeutic effects.