MRI-based measurements of aerosol deposition in the lung of healthy and elastase-treated rats

Abstract

Aerosolized drugs are increasingly being used to treat chronic lung diseases or to deliver therapeutics systemically through the lung. The influence of disease, such as emphysema, on particle deposition is not fully understood. With the use of magnetic resonance imaging (MRI), the deposition pattern of iron oxide particles with a mass median aerodynamic diameter of 1.2 μm was assessed in the lungs of healthy and elastase-treated rats. Tracheostomized rats were ventilated with particles, at a tidal volume of 2.2 ml, and a breathing frequency of 80 breaths/min. Maximum airway pressure was significantly lower in the elastase-treated (Paw = 7.71 ± 1.68 cmH2O) than in the healthy rats (Paw = 10.43 ± 1.02 cmH2O; P < 0.01). This is consistent with an increase in compliance characteristic of an emphysema-like lung structure. Following exposure, lungs were perfusion fixed and imaged in a 3T MR scanner. Particle concentration in the different lobes was determined based on a relationship with the MR signal decay rate, R2*. Whole lung particle deposition was significantly higher in the elastase-treated rats (CE,part = 3.03 ± 0.61 μm/ml) compared with the healthy rats (CH,part = 1.84 ± 0.35 μm/ml; P < 0.01). However, when particle deposition in each lobe was normalized by total deposition in the lung, there was no difference between the experimental groups. However, the relative dispersion [RD = standard deviation/mean] of R2* was significantly higher in the elastase-treated rats (RDE = 0.32 ± 0.02) compared with the healthy rats (RDH = 0.25 ± 0.02; P < 0.01). These data show that particle deposition is higher and more heterogeneously distributed in emphysematous lungs compared with healthy lungs.

Airflow and Particle Deposition Simulations in Health and Emphysema: From In Vivo to In Silico Animal Experiments

“…38,39 The global respiratory values, i.e. resistance and compliance, were estimated from the airway pressure and the breathing parameters measured during the experiments.…”

“…38,39 Five healthy and five elastase induced emphysematous 39 anesthetized rats (body weight of 409 ± 26 grams and 432 ± 46 grams, respectively) were mechanically ventilated. During inhalation, the piston pump pushed 2.2 mL of particle-laden air into the lung at a breathing frequency (BF) of 80 $1\frac{breaths}{min}$.…”

“…The 3D model ended at the distal airways, each corresponding to one of the five rat lobes. As the conducting airways were not influenced by emphysema, as confirmed by measuring the airway diameter from the MR images, 39 the same geometric model was used for the healthy and emphysema simulations. A custom stabilized finite element Navier-Stokes solver was employed to simulate airflow in the 3D model, assuming rigid walls and Newtonian flow with a density of $1.2\ast {10}^{-6}\frac{g}{m{m}^3}$ and viscosity of $1.81\ast {10}^{-5}\frac{g}{mm-s}$.…”

“…The aerosol particles were assumed to be inert and monodisperse with a diameter of 0.95 μm and density of 1.35 g cm −3 , to match the exposure experiment. 39 Additional particles with diameters of 3 and 5 μm were simulated. Equation (4) was solved analytically for $\overrightarrow{v}\left(x_j\left(t\right)\right)$, the velocity of the particle j at arbitrary time t i as a function of the other variables (namely $\overrightarrow{u}\left(t_i\right)$, obtained from linear space-time interpolation from the air velocity field mesh, and $\frac{D\overrightarrow{u}}{Dt}\left(t_i\right)$, obtained by linear interpolation of the air velocity field and a second order accurate central difference formula for the spatial and temporal derivatives).…”

“…39 In the experimental study, pressure was measured over time at the trachea and the maximum pressure was significantly lower (p = 0.01) in the emphysematous rats compared to the healthy rats. 39 In this current study, the global respiratory resistance and compliance were inferred by solving a well-known two-component lumped parameter model (0D global model) 4 from aerodynamics measurements taken during the exposure experiments. The multi-scale airflow simulations were then performed by coupling MRI-derived 3D rat conducting airways 37 to the 0D global model.…”