PhD, University of Cincinnati, 2021, Arts and Sciences: Physics

Newborns admitted to the neonatal intensive care unit can suffer from various respiratory diseases due to prematurity or abnormality. Tracheomalacia (TM) is an airway condition characterized by airway collapse during breathing. Newborns diagnosed with TM may require respiratory support for breathing and there is no reliable method to quantify the breathing effort. The standard diagnosis for TM is bronchoscopy. However, bronchoscopy cannot precisely evaluate the severity of the disease and measure the effect of airway motion on airflow. This study aims to quantify airflow measurements such as work of breathing, airway resistance, and pressure in the central airway (trachea and main bronchi). Magnetic resonance imaging (MRI) was used to obtain the airway anatomy and motion during the breathing cycle. The acquired MR images were reconstructed based on respiration to obtain four MR images that show four main breathing phases (end expiration, peak inspiration, end inspiration, and peak expiration). Airway surfaces were segmented from MR images to create virtual airway models. Surface registration between the airway surfaces at each phase of breathing was used to obtain the physiologic motion during the breathing cycle. However, MRI cannot quantify airflow measurements alone. Computational fluid dynamics (CFD) is a well-known technique to model the airflow in airway models derived from MRI. Virtual airway models, airflow rates and airway motion were obtained for each subject and used as inputs for the CFD simulation. The main bronchi's airflow rates were obtained using the lung tidal volumes and the free induction decay waveform. Using these techniques, three studies were performed to investigate the effect of TM on neonatal respiration. The first study investigates the effect of airway motion on breathing by comparing airflow measurements in dynamic airways with static airways in four subjects with TM and without TM. Results indicated that CFD simulations should be perfo (open full item for complete abstract)

Committee: David Mast Ph.D. (Committee Chair); Zackary Cleveland Ph.D. (Committee Member); L. C. R. Wijewardhana Ph.D. (Committee Member); Jason Woods Ph.D. (Committee Member) Subjects: Radiology

PhD, University of Cincinnati, 2020, Medicine: Molecular and Developmental Biology

Birth defects affecting the trachea and esophagus, including impaired tracheoesophageal (TE) separation and tracheal chondrogenesis, are relatively common and are sometimes associated with mutations in the Hedgehog (HH)/Gli signaling pathway. However, how normal TE separation occurs is unknown, and the pathogenesis of how HH/GLI mutations might result in TE congenital defects is unclear. The work presented in this dissertation defines a step-wise process of normal TE morphogenesis. This research also identifies that relatively high amounts of Gli transcriptional repression activity impairs multiple steps of TE separation, mimicking a human syndrome associated with an early truncating mutation in GLI3 that leads to relatively high levels of GLI3 transcriptional repression. Additionally, this work reveals that impaired tracheal chondrogenesis seen in patients with HH/GLI mutations is likely the result of significant reductions in the transcription factors Foxf1 and Sox9, which are also associated with tracheal chondrogenesis defects. Finally, we identify that Wnt and BMP signaling are disrupted in the presence of relatively high Gli transcriptional repressor activity during tracheal chondrogenesis.

Committee: Aaron Zorn Ph.D. (Committee Chair); Samantha Brugmann Ph.D. (Committee Member); Paul Kingma Ph.D. (Committee Member); Debora Sinner Ph.D. (Committee Member); Jeffrey Whitsett M.D. (Committee Member); Katherine Yutzey Ph.D. (Committee Member) Subjects: Developmental Biology

Doctor of Philosophy, The Ohio State University, 2005, Biomedical Engineering

The work presented herein describes the investigation in several key areas related to imaging and image-guided therapy. Each area is of interest for advancing the state of the art and development of new techniques in image-guided therapy. First, the rationale and approaches for microfabrication of microparticles is advanced. A technique for microfabrication of biodegradable mircorparticles of tailorable geometry and monodisperse size is described as well as efforts and the design of an experimental set-up to optimize production. The applications of such microparticles as drug delivery vehicles or as agents for embolization (or both as in chemoembolization) make them a promising technology in image-guided therapy. A second related focus of study is presented in the area of quantitative diagnostics. Combining imaging techniques and analysis algorithms can both identify and quantify disease states. Precise determination the extent of disease can be used to gage response to therapy, i.e. provide outcome measures to develop new therapies, including those advanced by image-guidance. A novel imaging method for identification of disease states of the major airways and lungs in pediatric populations is presented. Lastly, an animal model suitable for the testing of therapies directed against lymphatic malformations and lymphangiogenesis is presented. This method of site-specific induction of de novo lymphatic malformations (LMs) expressing specific growth factor receptors will allow investigations in the function and formation of lymphatic vessels. Macrocystic LMs observed in this model are shown to be large enough to target using current image-guided approaches (sclerotherapy) to optimize treatment capabilities. Microcystic LMs are also induced in this model, which might allow development of therapy against this variant. The LMs cysts have promise as bioreactors to test particle-based therapies directed against lymphatic endothelium. Each of the presented areas has bearing f (open full item for complete abstract)

Committee: Derek Hansford (Advisor) Subjects: