Graduation Year

2018

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Engineering

Major Professor

Christopher Passaglia, Ph.D.

Committee Member

Robert Frisina Jr., Ph.D.

Committee Member

Nathan Gallant, Ph.D.

Committee Member

Mark Jaroszeski, Ph.D.

Committee Member

Radouil Tzekov, M.D.

Keywords

Conventional Outflow Facility, Glaucoma, Intracranial Pressure, Intraocular Pressure, Ocular Hypertension

Abstract

Glaucoma affects tens of millions of people and is the leading cause of irreversible blindness worldwide. Virtually all current glaucoma therapies target elevated intraocular pressure (IOP); however, the contribution of intracranial pressure (ICP) to glaucoma has recently garnered interest. Strain at the optic nerve head is now known to depend on the translaminar pressure difference (TLPD), which is the difference between IOP and ICP, rather than IOP alone. A better understanding of how IOP and ICP relate to glaucoma development and progression is essential for developing improved therapies and diagnostic tests. Glaucoma is commonly modeled in rats, yet aqueous humor dynamics are not well-documented in healthy nor diseased rat eyes. Moreover, because rats do not develop glaucoma spontaneously, it is essential to develop low-cost, reliable, and relevant models of glaucomatous pathology in the animal.

The purpose of this dissertation work is to achieve the following goals: i) quantitatively assess aqueous humor dynamics in healthy, living rat eyes, ii) develop an ideal model of experimental glaucoma in rats, iii) quantitatively characterize aqueous humor dynamics throughout experimental glaucoma in living rats, and iv) investigate the effects of ICP manipulations on aqueous humor dynamics in living rats. Chapter 2 reports physiological parameters of aqueous humor dynamics for the first time in the eyes of living, healthy Brown-Norway rats, and presents a novel perfusion technique for efficiently and accurately estimating these parameters. Chapter 3 introduces the constant-pressure perfusion model of experimental glaucoma: a powerful new model which overcomes several limitations of existing techniques. The constant-pressure perfusion model induces IOP elevations which are prescribable and easily manipulated, does not directly target the trabecular meshwork or its vasculature, and offers continuous records of IOP rather than requiring regular animal handling and tonometry. Chapter 3 characterizes IOP-induced optic neuropathies in rats and demonstrates their resemblance to human glaucoma. Chapter 4 evaluates whether the constant-pressure perfusion model affects ocular physiology, specifically showing that resting IOP and conventional outflow facility are not permanently nor significantly altered in the model. Chapter 5 examines the effect of ICP manipulations on aqueous outflow physiology in living rats, and reports for the first time a graded effect of intracranial hypertension on conventional outflow facility. Evidence for a neural feedback mechanism that may serve to regulate the TLPD is also presented. Chapter 6 summarizes the results of this dissertation, provides recommendations for future work, and gives closing remarks.

These collective projects provide insight into IOP regulation in both healthy and diseased rat eyes, advancing our understanding of glaucomatous development and damage in rats. A novel model of experimental glaucoma and several perfusion systems have been developed which are distinctly tailored for use in future glaucoma studies and will allow future investigators to study the disease with enhanced efficiency and exactitude. The results of this dissertation work suggest that detecting and correcting impairments of either IOP or ICP homeostatic capabilities may be of utmost importance for improving clinical outcomes in human glaucoma.

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