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Towards Personalized Medicine in Cystic Fibrosis: Patient-Specific Modeling of Mucociliary Clearance Using Physiologically-Based Flow Constraints

Shapiro, Monica E (2023) Towards Personalized Medicine in Cystic Fibrosis: Patient-Specific Modeling of Mucociliary Clearance Using Physiologically-Based Flow Constraints. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Healthy humans have a thin layer of mucus lining the airways that protects the lungs
from inhaled particulate or pathogens. Trapped particles are conveyed up the airway tree
and out of the lungs by tiny, hair-like structures called cilia in a process called mucociliary
clearance (MCC). Cystic fibrosis (CF) is a rare, lethal, genetic disease that dehydrates this
mucus layer and disrupts MCC. This causes chronic infection and inflammation, leading to
respiratory failure. Typical treatment for CF takes about 2 hours a day, creating a high
treatment burden and leading to poor compliance. With the development of highly-effective
modulators that target underlying defects of CF has come a push to reduce treatment burden.
One time-consuming therapy that is widely used is aerosolized hypertonic saline (HS). HS
aims to rehydrate airway mucus and improve MCC, however, the efficacy varies greatly
between individuals. This creates a need for new screening tools to predict HS efficacy on a
per-patient basis, which is the focus of this dissertation.
MCC in different sections of the airway tree varies, even within an individual. We thus
developed a physiologically-based dynamic model of MCC that captured local variability
within the lung. The granularity of the model enabled identification of focal defects, but
had poor parameter identifiability. We reduced the number of free parameters to improve
identifiability, while preserving the physiological constraints. The reduced model contained
5 free parameters and only increased the mean absolute error per grid by 8.7% from the
original 114-parameter model. Finally, we fit this model to nuclear imaging data from CF
participants on two separate days: one where they inhaled non-therapeutic isotonic saline
and one where they inhaled HS. We developed a statistical model to estimate the parameter
change after HS treatment for these participants based clinical and in vitro measurements.
The end result was a tool that can be used to estimate personalized MCC response of CF
individuals to HS treatment


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Shapiro, Monica Emos57@pitt.edumos57
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairParker, Robert
Committee CoChairCorcoran, Timothy
Committee MemberBertrand, Carol
Committee MemberShoemaker, Jason
Committee MemberCole, Daniel
Date: 14 September 2023
Date Type: Publication
Defense Date: 24 May 2023
Approval Date: 14 September 2023
Submission Date: 1 August 2023
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 160
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Chemical and Petroleum Engineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: mucociliary clearance, cystic fibrosis, planar scintigraphy
Date Deposited: 14 Sep 2023 13:45
Last Modified: 14 Sep 2023 13:45


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