DOI

10.17077/etd.vikke6ad

Document Type

Thesis

Date of Degree

Spring 2017

Access Restrictions

Access restricted until 07/13/2019

Degree Name

MS (Master of Science)

Degree In

Mechanical Engineering

First Advisor

Lin, Ching-Long

Second Advisor

O'Shaughnessy, Patrick

First Committee Member

Buchholz, James

Second Committee Member

Hoffman, Eric A.

Abstract

Aerosolized drug delivery to the human lungs for asthma treatment has long been studied and yet the relationship between the delivery efficacy and the inter-subject variability due to gender, age, and disease severity remains unclear. A recent imaging-based cluster analysis on a population of asthmatic patients identifies four clusters with distinct structural and functional characteristics. The use of cluster membership to explore inter-subject variability by investigating numerically the air flow and particle transport in representative subjects of the asthmatic clusters on inhalation drug delivery in asthma sub-populations is proposed. Large-eddy simulations using computed tomography (CT)-based airway models were performed with a slow and deep breathing profile corresponding to application of a metered dose inhaler. Physiologically consistent subject specific boundary conditions in peripheral airways were produced using an image registration technique and a resistance network compliance model. Particle simulations and final deposition statistics were calculated for particle sizes ranging from 1–8 μm. The results suggested an emphasis on the importance of airway constriction for regional particle deposition and prominent effects of local features in lobar, segmental, and sub-segmental airways on overall deposition patterns. Asthmatic clusters characterized by airway constriction had an increase in deposition efficiency in lobar, segmental, and sub-segmental airways. Local constrictions produced jet flows that impinged on distal bifurcations and resulted in large inertial depositions. Decreased right main bronchus (RMB) branching angle decreased the fraction of particles ventilated to the right upper lobe (RUL). Cluster-based computational fluid dynamics results demonstrate particle deposition characteristics associated with imaging based variables that could be useful for future drug delivery improvements.

One method for circumventing low deposition in small airways due to constriction in tracheobronchial airways is through hygroscopic growth of aerosols for inhalation. Hygroscopic materials have an affinity for water and can enlarge in size significantly as they traverse through respiratory tract. Hygroscopic growth has shown promise as a viable drug delivery method for decreasing deposition in the upper tracheobronchial region and increasing drug penetration and retention in small airways. Current models for hygroscopic growth models show promise in predicting steady state final diameter aerosol droplet sizes, but much uncertainty in predicting transient effects exists. This paper discusses in detail one such growth model and modifies it to include realistic spatial temperature and humidity variations associated with the lung. The growth model is simplified through grouping of terms and is then solved using MATLAB ODE 45 solver. The model is compared to experimentally acquired in vitro data for validation. The results do not show good agreement with the model, and suggests that additional factors exist that inhibit aerosol droplet growth from commencing immediately upon entering the respiratory tract like is assumed true in literature. This paper briefly hypothesizes for reasons for model and data disagreement and limitations of current growth models.

Public Abstract

Subject variability has long been a limitation of improved asthma drug delivery. Asthmatic lungs contain a variety of characteristics that are not present in all patients. These characteristics have implications on effectiveness of drug delivery and provide variability challenges for drug development. A new method for characterizing asthma sub-groups subjects into clusters uses CT-image based characteristics in conjunction with clinical information. The clustering allows for simulation of group representative subjects to investigate the mechanics of group specific variables on air and particle transport. The results demonstrate an emphasis on airway constriction for regional deposition. Subjects with constriction had increased deposition in upper airways. Simulation results conclude that cluster structural characteristics based on CT-imaging could be useful for future drug delivery improvements. Airway constriction was found to hinder drug delivery and penetration to the deep portions of the lungs.

A promising method for circumventing airways constriction and allowing greater penetration of drugs into the deep lung is through growing inhaled aerosols through water absorption in the respiratory tract. Current growth models predict steady state final aerosol sizes well, however much uncertainty exists in modeling the transient growth leading up to final size. This paper discusses one such growth model and suggests a method for improving the quality of predictions for lung application. Model results of transient growth do not agree with experimental data suggesting unaccounted factors at play that inhibit growth. This paper discusses current model limitations and the need for improvement for application to pulmonary drug delivery use.

Keywords

Asthma, CFD, Multi-scale, Particle transport, Pulmonary flow

Pages

x, 91 pages

Bibliography

Includes bibliographical references (pages 80-85).

Copyright

Copyright © 2017 Lawrence Joseph LeBlanc

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