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Access Type

WSU Access

Date of Award

January 2025

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biomedical Engineering

First Advisor

Carolyn A. Harris

Abstract

Hydrocephalus is a neurological condition characterized by the buildup of cerebrospinal fluid (CSF) in the ventricles of the brain, causing increased intracranial pressure (ICP) and dilatation of the ventricles. The estimated incidence of hydrocephalus in the United States is 1 per 1100 people. The current gold-standard of treatment is ventricular shunting. Patients have a severely diminished quality of life and suffer from long-term neurologic deficits because of the high failure rate of ventricular shunts; of the 30,000 shunts placed annually in the United States, 98% fail within ten years. A major cause of failure is the obstruction of ventricular catheters (VC) by tissue, restricting its drainage of CSF. Although multiple studies have tried to identify factors that cause VC failure, the mechanisms by which tissue obstructs the holes of the VC are not completely understood. Additionally, no successful non-surgical or pharmacological treatment strategies exist, primarily because we do not understand how CSF secretion is modulated by the choroid plexus (CP). Specifically, we need to understand the role of the CP’s ion and water transporters in CSF secretion, and their dysregulation by hydrocephalus-induced inflammation. To address these issues, we chose a two-pronged approach to the problem of hydrocephalus treatment: reforming the current gold standard of treatment (shunts), and revolutionizing treatment strategies by building a model to understand CSF secretion.

In the first prong of this work, we characterized VC obstructions and identified links to clinical factors. 343 VCs and their associated clinical data were collected from five hospital centers. Each hole on the VCs was classified by degree of tissue obstruction and subjected to microscopic analysis. Univariate, multivariate, and binned analyses were conducted to test for associations between clinical data and degree of VC obstruction. Our data show that the age of the patient at their first surgery, entry site of the VC, contact of the VC with the ventricular wall and length of time a VC is implanted are factors that influence the degree of VC obstruction. Number of lifetime revisions and duration of implantation are correlated with the degree of VC obstruction, but do not predict it. We also explored the relationship between ventricular obstruction and ventricular dilation and flow through the holes of the catheter. The tissue aggregates obstructing VCs are composed predominantly of astrocytes and macrophages.

In the second prong of this work, we developed a “CP-on-a-chip”, a microfluidic, 2-compartment model of the blood-cerebrospinal fluid barrier. The model provides the mechanical cue of physiological shear in the luminal and abluminal compartments, maintains physiologically accurate tissue-fluid ratios and allows us to track and manipulate secretion and barrier function of the CP. Immunofluorescent labeling has confirmed that CP epithelial cells grown inside the abluminal compartment orient themselves correctly and express critical tight junction components, establishing a low permeability, monolayer. We have also successfully simulated secretion of fluid across compartments. Future work involves studying inflammation mediated barrier integrity loss and subsequent CSF dysregulation as it pertains to hydrocephalus.

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