Estimating Human Trabecular Meshwork Stiffness by Numerical Modeling and Advanced OCT Imaging

Abstract

PurposeThe purpose of this study was to estimate human trabecular meshwork (hTM) stiffness, thought to be elevated in glaucoma, using a novel indirect approach, and to compare results with direct en face atomic force microscopy (AFM) measurements.MethodsPostmortem human eyes were perfused to measure outflow facility and identify high- and low-flow regions (HF, LF) by tracer. Optical coherence tomography (OCT) images were obtained as Schlemm's canal luminal pressure was directly manipulated. TM stiffness was deduced by an inverse finite element modeling (FEM) approach. A series of AFM forcemaps was acquired along a line traversing the anterior angle on a radially cut flat-mount corneoscleral wedge with TM facing upward.ResultsThe elastic modulus of normal hTM estimated by inverse FEM was 70 ± 20 kPa (mean ± SD), whereas glaucomatous hTM was slightly stiffer (98 ± 19 kPa). This trend was consistent with TM stiffnesses measured by AFM: normal hTM stiffness = 1.37 ± 0.56 kPa, which was lower than glaucomatous hTM stiffness (2.75 ± 1.19 kPa). None of these differences were statistically significant. TM in HF wedges was softer than that in LF wedges for both normal and glaucomatous eyes based on the inverse FEM approach but not by AFM. Outflow facility was significantly correlated with TM stiffness estimated by FEM in six human eyes (P = 0.018).ConclusionsTM stiffness is higher, but only modestly so, in glaucomatous patients. Outflow facility in both normal and glaucomatous human eyes appears to associate with TM stiffness. This evidence motivates further studies to investigate factors underlying TM biomechanical property regulation.

A tissue-engineered human trabecular meshwork hydrogel for advanced glaucoma disease modeling

“…DEX treatment significantly stiffened HTM hydrogels vs. control (~1.7-fold) consistent with recent reports from normal and glaucomatous HTM tissues 13,67 , while Y27632 had precisely opposite effects and significantly softened HTM hydrogels vs. controls (~0.6-fold). No differences were observed between DEX + Y27632 co-treatment and controls.…”

“…Dysregulation of HTM cells and pathologic ECM remodeling jointly contribute to HTM stiffening in POAG, which negatively affects IOP in a feed-forward loop [11][12][13] . To assess the functional consequences of increased hydrogel contraction/condensation, driven by cytoskeletal rearrangements and ECM remodeling/deposition, on tissue-level construct stiffness, we next performed rheology analysis of HTM hydrogels subjected to the different treatments.…”

“…Patients with POAG, the most common subtype of glaucoma, typically suffer from elevated IOP and experience increased HTM stiffness, which in turn can negatively affect IOP and HTM cell function in a feed-forward loop [9][10][11][12][13] . It is perhaps because of these observations that more studies in recent years have focused on the biomechanical properties of tissues within the conventional outflow pathway, and their dynamic changes in disease.…”

“…Several limitations to this study, however, may have resulted in overestimated differences in tissue elasticity. In a recent elegant study using a novel indirect approach (with AFM correlation), HTM stiffness was determined to be ~1.4-fold greater in glaucomatous HTM tissues vs. normal controls 13,67 . The discrepancies in both absolute and relative stiffness values (i.e., normal vs. glaucomatous) between the two studies most likely stem from methodological differences.…”

“…Prolonged elevation of IOP causes pathologic distension and compression of the HTM and further tissue stiffening. Consequently, the stiffened HTM negatively affects IOP and HTM cell function in a feed-forward loop [11][12][13] . Since elevated IOP is a primary risk factor for glaucoma, this pathologic process leads to retinal ganglion cell damage resulting in the irreversible loss of vision that is characterized as primary open-angle glaucoma (POAG), the most common form of glaucoma [14][15][16][17][18] .…”