(516e) Predict the Effect of Disease-Specific Airway Deformation Kinematics on Dry Powder Transport and Deposition in Whole Lung

Jianan Zhao ^b, Ahmadreza Haghnegahdar ^c, and Rahul Bharadwaj ^c , Yu Feng ^b

^b School of Chemical Engineering, Oklahoma State University, Stillwater, OK 74078, USA

^c ESSS Inc., Woburn, MA 01801, USA

Introduction

As a key category of orally inhaled drug products (OIDPs), dry powder inhalers (DPIs) deliver active pharmaceutical ingredients (APIs) via the inhalation route to treat asthma and chronic obstructive pulmonary disease (COPD). Providing accurate predictions of regional deposition of orally inhaled drug products (OIDPs) is essential for demonstrating in-vitro in-vivo correlation (IVIVC), i.e., in vitro metrics and regional lung depositions, of locally acting generic DPI products. Although Computational Fluid-Particle Dynamics (CFPD) models have been done on such predictions, there is one critical deficiency in existing in silico whole-lung models, i.e., static airway wall position is assumed by neglecting physiologically realistic airway deformation kinematics. Neglecting the physiologically realistic airway deformation can lead to errors in the predictions of air-particle transport phenomena, and disable the capability to predict the influence of disease-specific airway deformation kinematics on pulmonary air-particle flow structures. To address the modeling deficiency, a well-calibrated and validated elastic whole-lung modeling framework has been developed to improve the physiological realism of lung deposition prediction with the disease-specific lung environments. Using the elastic whole-lung model, The objective of this study to answer the following two fundamental questions in pulmonary drug delivery, i.e., (1) How can disease-specific real-time airway deformation kinematics alter the pulmonary airflow features (i.e., laminar-to-turbulence transition, and relaminarization) and particle distribution, thereby influencing the particle trajectories and deposition sites in the lung? (2) How can the coordination between DPI and patients be modulated to overcome the significant drug loss due to the upper airway deposition caused by turbulence dispersion, inertial impaction, and interception with the moving airway boundaries, thereby enhancing the particle delivery efficiency to distal airways that have undergone the loss of lung expansion and contraction capability?

Material and Methods: The New Elastic Whole-Lung Modeling Framework

Driven by the diaphragm movement in the physiologically realistic condition, the tracheobronchial (TB) tree consistently deforms following rhythmical expansion and contraction motions during breathing. A new elastic whole-lung model has been developed for this study to recover the real-time anisotropic lung deformation from mouth to alveoli is necessary to reflect disease-specific lung elasticities and generate accurate airflow and particle transport dynamics. The elastic truncated whole-lung (TWL) model (see Fig. 1) consists of four parts, i.e., mouth-throat (MT), upper tracheobronchial (UTB) airways extending through the first generation (second bifurcations), lower tracheobronchial (LTB) airways, and alveoli. The first three parts thereby represent the conductive airway zone extending from the mouth to the lowest bronchioles right before the start of the alveolar region. The airway deformation kinematics was achieved by applying the prescribed dynamic mesh method. Specifically, the movement of cell element nodes of the TWL model were controlled using the matrices transformations method, which was realized by a user-defined function (UDF) complied in Ansys Fluent (Ansys Inc., Canonsburg, PA). Specifically, the “smoothing-diffusion” dynamic mesh method was applied to achieve the node movement. The airway wall from the trachea to generation 17 (G17) expanded and constricted in all three directions (arm-arm (y) direction, head-foot (x), and back-front (z) directions) with a deformation ratio of x:y:z = 1:1:0.375. Also, the expansion and contraction of the alveoli were assumed to be isotropic and the deformation ratio was determined by matching the lung volume during breathing measured by the clinical experiments. Furthermore, the glottis abduction and adduction motion was also modeled simultaneously in the y-direction. We have optimized and validated the deformation kinematics of the elastic TWL model by matching clinical data of disease-specific lung volume variations. Disease conditions include chronic obstructive pulmonary diseases (COPDs) at different GOLD Stages, i.e., from mild to severe.

Expected Results and Discussion

The aerodynamic particle size distributions (APSDs) emitted from Spiriva^TMHandihaler^TM our previous numerical studies [9] using discrete element method (DEM), associated with different actuation flow rates and particle shapes. Since APSD is one of the critical factors that can influence the localized particle deposition patterns in human respiratory systems, simulations for parametric analyses are running with different APSDs as the particle inlet conditions (see Step 1 in Fig. 2).

Specifically, with the elastic lung models representing different disease conditions, we will determine how COPD progression influences the airway deformation and the resultant air-particle dynamics in airways (see Step 2 in Fig. 2). COPD condition leads to variations in three parameters, i.e., the airway diameter, breathing patterns/ventilation conditions, and airway deformation kinematics. They can simultaneously influence pulmonary air-particle flow dynamics. To decouple the influences of the three parameters, we will use both rigid and elastic COPD whole-lung models to quantify the decoupled influences. First, simulations will be performed in the rigid COPD whole-lung model, inhaling particles with the APSDs predicted in Step 1 (see Fig. 2). We will first assume the flow rate distributions among the five lobes are identical between the COPD and healthy whole-lung models. This set of simulations is to decouple the influences of airway diameter change from the ventilation condition change. Secondly, we will employ COPD-specific flow rate distributions plus the artificially created flow rate distributions, repeat the simulations in the rigid COPD models, and manifest the influence of ventilation condition change. Finally, simulations will be done in elastic COPD and healthy whole-lung models to quantify the impact of COPD-induced shifts (from GOLD Stage I to IV) of airway deformation kinematics on pulmonary air-particle flow dynamics from mouth to alveoli. Differences will be quantified in airflow fields, particle distributions, and deposition patterns and mechanisms. We will determine how the four breathing features can influence the vortex structure and velocity field in human respiratory systems, and how the variations of the airflow patterns can alter the particle transport and deposition mechanisms. Accordingly, we will find the optimized DPI-patient coordination and disease factors with the maximum regional deposition fractions in small airways first, then determine the optimized breathing waveforms that can further improve the targeted delivery efficiency for particles with the same inhaled APSDs. Also, easy-to-use correlations of DFs in small airways as a function of COPD disease condition, capsule design, drug properties, and coordination with the patients will be provided to facilitate the disease-specific drug design for targeted delivery.

Expected Conclusions

A novel elastic whole-lung modeling framework has been developed and validated, with the capability to model the physiologically realistic airway deformation kinematics coupled with the air-particle flow transport and deposition through pulmonary routes. It is the first whole-lung model with disease-specific airway deformation kinematics that accurately evaluate disease-specific pulmonary drug-device performances, generating personalized, comprehensive, and high-resolution pulmonary transport and deposition data. Upon completion of this study, the new elastic whole-lung model simulation results will manifest the underlying air-particle dynamics on how COPD-induced lung morphological and airway elasticity changes can influence the transport and delivery of inhaled drug particles emitted from the representative DPI in the whole lung from mouth to alveoli. The “all-in-one” in silico tool shown in Fig. 2, combining CFD and DEM models, will provide sufficient digital evidence and enable cost-effective and time-saving in vitro-regional deposition correlations and build more predictive IVIVC on a disease-specific level. New insights can be obtained for product development and bioequivalence assessments and further clarify regulatory expectations for generic DPI product development with more confidence based on the enhanced physiological realism.

Acknowledgments

The research was made possible by funding through the award for project number HR19-106, from the Oklahoma Center for the Advancement of Science and Technology. The use of Rocky DEM (ESSS, Woburn, MA) as part of the ESSS-CBBL academic partnership is gratefully acknowledged (Dr. Rahul Bharadwaj). The use of Ansys software (Ansys Inc., Canonsburg, PA) as part of the Ansys-CBBL academic partnership is also gratefully acknowledged (Dr. Thierry Marchal).