Measuring the Effects of Structure on the Deformation of the Optic Nerve

Thao Nguyen, PhD
Johns Hopkins University (Baltimore, MD)

Co-Principal Investigators

Harry Quigley, MD
Johns Hopkins University School of Medicine (Baltimore, MD)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to December 30, 2017
Disease:
Glaucoma
Award Amount:
$99,911
Grant Reference ID:
G2015132
Award Type:
Standard
Award Region:
US Northeastern

This grant is made possible in part by a bequest from the Margaret Louise Rigby Trust.

Thao Nguyen, PhD

Biomechanics of the Optic Nerve Head: Measuring the Effects of Chemical Treatments Altering Connective Tissue Properties

Summary

Intraocular pressure (IOP) is a major risk factor for the development and severity of glaucoma.  This project investigates the biomechanical environment of the human optic nerve head as it is affected by IOP with the goal of understanding the connection between IOP and glaucoma. Moreover, the project aims to measure how the biomechanical environment of the optic nerve head can be altered by chemical treatments that stiffen or soften the eye-wall for neuroprotection.  The implications of this work will be important for helping us better understand the susceptibility of individuals to glaucoma; for developing new diagnostic techniques that, for example, measure a key mechanical property of the sclera and lamina cribrosa (LC); and for developing new therapeutic strategies.

Details

Intraocular pressure plays an important role in the development of glaucomatous neuropathy. Studies have shown that higher IOP is associated with an increase in the incidence of glaucoma and in the severity of glaucoma damage to the optic nerve axons. Lowering the intraocular pressure is effective at slowing the progression of glaucoma damage. However, the level of IOP, all alone, is not associated with glaucoma. Individuals with pressures higher than the population average may not develop glaucoma, and a significant percentage of glaucoma patients have normal or low IOP.

The goal of this research is to understand how the tissues of the optic nerve head may become deformed by the level of IOP, and also the effect of the tissue structure and composition on the pressure-induced deformation of the optic nerve tissues. 

Deformation of the optic nerve tissues can damage axons, directly and indirectly, by distorting the capillaries, which decreases blood flow, and by activating pathological functions of cells in the lamina cribrosa. The level of pressure-induced deformation in the optic nerve head depends on the mechanical behavior of the sclera and lamina cribrosa. This may help explain why glaucoma sometimes develops in individuals with low IOP but not in others with high IOP. Also, there is a growing interest in developing therapies that alter the mechanical properties of the posterior eye-wall to reduce the strain in the optic head and slow the progression of glaucoma damage.

Numerous studies have demonstrated the ability to stiffen the sclera using glyceraldehyde and other collagen crosslinking agents and to soften the tissue through enzymatic degradation. Dr. Nguyen, along with Harry A Quigley, MD, of Johns Hopkins, have hypothesized that the chemical treatments produce different degrees of stiffening and softening in the lamina cribrosa and sclera because of individual differences in the structure of these connective tissues. This differential change in the stiffness of the lamina cribrosa and sclera will change the level of deformation in the optic nerve tissues. To test this hypothesis, Drs. Nguyen and Quigley have developed an experiment that uses advanced nonlinear optical microscopy and image correlation analysis to measure the deformation of the lamina cribrosa from controlled pressurization.  The imaging method allows simultaneous measurements of the collagen structure, and the investigators will analyze these data for correlations between the structure and deformation.  Drs. Nguyen and Quigley will also develop experiments to stiffen the lamina cribrosa and sclera with glyceraldehyde, a collagen crosslinker, and will experiment with softening the tissues by degrading the sulfated glycosaminoglycans. They will measure the effect of the chemical treatments on the deformation of the lamina cribrosa.

This study will provide a fundamental understanding of how individual variations in the connective tissue structure influence the deformation of the lamina cribrosa caused by IOP. Moreover, the study will provide insight into the neuroprotective potential of modifying connective tissue properties using glyceraldehyde and chondroitinase, as well as provide an experimental method for screening the effectiveness of new chemical agents.

About the Researcher

Thao (Vicky) Nguyen, PhD, is an associate professor in the Departments of Mechanical Engineering and Materials Science at The Johns Hopkins University in Baltimore. Dr. Nguyen obtained her Bachelor of Science degree in mechanical engineering from MIT in 1998, and an MS and PhD in mechanical engineering from Stanford University, Palo Alto, Calif., in 2004. She worked as a research scientist at Sandia National Laboratories in Livermore, Calif., before joining Johns Hopkins in 2007. Her research focuses on the biomechanics of soft tissues and mechanics of stimuli-responsive polymers. Dr. Nguyen has received numerous awards, including the 2008 Presidential Early Career Award for Scientists and Engineers and the National Science Foundation Career Award (2013) to investigate growth and remodeling of collagenous tissues.



"I am a mechanical engineer by training. My PhD dissertation was on the fracture of polymers, and was completely unrelated to biomechanics. However, at conferences and through interactions with colleagues, I was struck by the beauty and optimality in the design of soft tissues, especially those of the eyes. The microstructure of connective tissues of the eye rivals that of the most advanced engineering fiber composites. As an engineer, I wanted to understand how the structure of these tissues supports the function of the human vision system, and how we can leverage this understanding to develop more advanced diagnostics and therapies for glaucoma."

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