Mechanical properties of trabecular meshwork

Glaucoma is the second leading cause of blindness. However, the precise mechanisms leading to vision loss in this disease remain unknown. Increased intraocular pressure (IOP) has been recognized as the most important risk factor, and lowering IOP is currently the only effective treatment for glaucoma. Unfortunately, pressure lowering usually only slows progression and does not cure the disease. The mechanical properties of the trabecular meshwork (TM) have been suggested to differ significantly between glaucomatous eyes versus unaffected eyes. This is important because the TM has a major influence on IOP. The objective of this work is to develop computer modeling and experimental tools to characterize TM stiffness in situ for human and mouse eyes, and to evaluate the role of mechanical properties of TM in influencing IOP across different conditions. We developed an inverse finite element method to estimate TM stiffness in dissected anterior wedges from 6 normal and 5 glaucomatous human eyes, in combination with optical coherence tomography (OCT) imaging. The results obtained from this method were also compared to direct measurements using atomic force microscopy (AFM). We showed that TM stiffness was higher, but only modestly so, in glaucomatous patients. Interestingly, outflow facility in both normal and glaucomatous human eyes appeared to associate with TM stiffness. We then went on to study TM in mice, first developing a cryosection-based AFM technique to localize and directly measure compressive Young’s modulus of TM. We found a significant correlation between TM stiffness and outflow resistance in wild-type mice. Further, we found that local DEX treatment in live mice can induce higher IOP and stiffer TM, and that a significant correlation between TM stiffness and outflow resistance also existed in DEX-treated mice. Together these findings suggest that TM stiffness might be a surrogate marker for conventional outflow pathway function. This work motivates development of therapies to alter TM stiffness, or the factors underlying TM biomechanical property regulation, as potential novel alternative treatments for control of ocular hypertension in glaucoma.Ph.D