Abstract

Glaucoma is the second leading cause of blindness worldwide and is characterized by the death of retinal ganglion cells (RGCs), the cells that send vision information to the brain. Their axons exit the eye at the optic nerve head (ONH), the main site of damage in glaucoma. The importance of biomechanics in glaucoma is indicated by the fact that elevated intraocular pressure (IOP) is a causative risk factor for the disease. However, exactly how biomechanical insult leads to RGC death is not understood. Although rat models are widely used to study glaucoma, their ONH biomechanics have not been characterized in depth. Therefore, we aimed to do so through finite element (FE) modeling. Utilizing our previously described method, we constructed and analyzed ONH models with individual-specific geometry in which the sclera was modeled as a matrix reinforced with collagen fibers. We developed eight sets of scleral material parameters based on results from our previous inverse FE study and used them to simulate the effects of elevated IOP in eight model variants of each of seven rat ONHs. Within the optic nerve, highest strains were seen inferiorly, a pattern that was consistent across model geometries and model variants. In addition, changing the collagen fiber direction to be circumferential within the peripapillary sclera resulted in more pronounced decreases in strain than changing scleral stiffness. The results from this study can be used to interpret data from rat glaucoma studies to learn more about how biomechanics affects RGC pathogenesis in glaucoma.

References

1.
Campbell
,
I. C.
,
Coudrillier
,
B.
, and
Ethier
,
C. R.
,
2014
, “
Biomechanics of the Posterior Eye: A Critical Role in Health and Disease
,”
ASME J. Biomech. Eng.
,
136
(
2
), p.
021005
.10.1115/1.4026286
2.
Sigal
,
I. A.
,
Flanagan
,
J. G.
,
Tertinegg
,
I.
, and
Ethier
,
C. R.
,
2004
, “
Finite Element Modeling of Optic Nerve Head Biomechanics
,”
Invest. Ophthalmol. Visual Sci.
,
45
(
12
), pp.
4378
4387
.10.1167/iovs.04-0133
3.
Sigal
,
I. A.
,
Flanagan
,
J. G.
,
Tertinegg
,
I.
, and
Ethier
,
C. R.
,
2009
, “
Modeling Individual-Specific Human Optic Nerve Head Biomechanics. Part I: IOP-Induced Deformations and Influence of Geometry
,”
Biomech. Model. Mechanobiol.
,
8
(
2
), pp.
85
98
.10.1007/s10237-008-0120-7
4.
Hua
,
Y.
,
Voorhees
,
A. P.
, and
Sigal
,
I. A.
,
2018
, “
Cerebrospinal Fluid Pressure: Revisiting Factors Influencing Optic Nerve Head Biomechanics
,”
Invest. Ophthalmol. Visual Sci.
,
59
(
1
), pp.
154
165
.10.1167/iovs.17-22488
5.
Burgoyne
,
C. F.
,
2011
, “
A Biomechanical Paradigm for Axonal Insult Within the Optic Nerve Head in Aging and Glaucoma
,”
Exp. Eye Res.
,
93
(
2
), pp.
120
132
.10.1016/j.exer.2010.09.005
6.
Yang
,
H.
,
Reynaud
,
J.
,
Lockwood
,
H.
,
Williams
,
G.
,
Hardin
,
C.
,
Reyes
,
L.
,
Stowell
,
C.
,
Gardiner
,
S. K.
, and
Burgoyne
,
C. F.
,
2017
, “
The Connective Tissue Phenotype of Glaucomatous Cupping in the Monkey Eye—Clinical and Research Implications
,”
Prog. Retinal Eye Res.
,
59
, pp.
1
52
.10.1016/j.preteyeres.2017.03.001
7.
Alqawlaq
,
S.
,
Flanagan
,
J. G.
, and
Sivak
,
J. M.
,
2018
, “
All Roads Lead to Glaucoma: Induced Retinal Injury Cascades Contribute to a Common Neurodegenerative Outcome
,”
Exp. Eye Res.
,
183
, pp.
88
97
.10.1016/j.exer.2018.11.005
8.
Anderson
,
D. R.
,
2003
, “
Collaborative Normal Tension Glaucoma Study
,”
Curr. Opin. Ophthalmol.
,
14
(
2
), pp.
86
90
.10.1097/00055735-200304000-00006
9.
Sigal
,
I. A.
,
Bilonick
,
R. A.
,
Kagemann
,
L.
,
Wollstein
,
G.
,
Ishikawa
,
H.
,
Schuman
,
J. S.
, and
Grimm
,
J. L.
,
2012
, “
The Optic Nerve Head as a Robust Biomechanical System
,”
Invest. Ophthalmol. Visual Sci.
,
53
(
6
), pp.
2658
2667
.10.1167/iovs.11-9303
10.
Morrison
,
J. C.
,
Cepurna
,
W. O.
,
Tehrani
,
S.
,
Choe
,
T. E.
,
Jayaram
,
H.
,
Lozano
,
D. C.
,
Fortune
,
B.
, and
Johnson
,
E. C.
,
2016
, “
A Period of Controlled Elevation of IOP (CEI) Produces the Specific Gene Expression Responses and Focal Injury Pattern of Experimental Rat Glaucoma
,”
Invest. Opthalmol. Visual Sci.
,
57
(
15
), p.
6700
.10.1167/iovs.16-20573
11.
Morrison
,
J. C.
,
Cepurna Ying Guo
,
W. O.
, and
Johnson
,
E. C.
,
2011
, “
Pathophysiology of Human Glaucomatous Optic Nerve Damage: Insights From Rodent Models of Glaucoma
,”
Exp. Eye Res.
,
93
(
2
), pp.
156
164
.10.1016/j.exer.2010.08.005
12.
Pazos
,
M.
,
Yang
,
H.
,
Gardiner
,
S. K.
,
Cepurna
,
W. O.
,
Johnson
,
E. C.
,
Morrison
,
J. C.
, and
Burgoyne
,
C. F.
,
2015
, “
Rat Optic Nerve Head Anatomy Within 3D Histomorphometric Reconstructions of Normal Control Eyes
,”
Exp. Eye Res.
,
139
, pp.
1
12
.10.1016/j.exer.2015.05.011
13.
Schwaner
,
S. A.
,
Kight
,
A. M.
,
Perry
,
R. N.
,
Pazos
,
M.
,
Yang
,
H.
,
Johnson
,
E. C.
,
Morrison
,
J. C.
,
Burgoyne
,
C. F.
,
R.
, and
Ethier
,
C.
,
2018
, “
A Methodology for Individual-Specific Modeling of Rat Optic Nerve Head Biomechanics in Glaucoma
,”
ASME J. Biomech. Eng.
,
140
(
8
), p.
084501
.10.1115/1.4039998
14.
Schwaner
,
S. A.
,
Hannon
,
B. G.
,
Feola
,
A. J.
, and
Ethier
,
C. R.
,
2020
, “
Biomechanical Properties of the Rat Sclera Obtained With Inverse Finite Element Modeling
,”
Biomech. Model. Mechanobiol.
,
19
, pp.
2195
2212
.10.1007/s10237-020-01333-4
15.
Sigal
,
I. A.
,
Flanagan
,
J. G.
, and
Ethier
,
C. R.
,
2005
, “
Factors Influencing Optic Nerve Head Biomechanics
,”
Invest. Ophthalmol. Visual Sci.
,
46
(
11
), pp.
4189
4199
.10.1167/iovs.05-0541
16.
Downs
,
J. C.
,
Yang
,
H.
,
Girkin
,
C.
,
Sakata
,
L.
,
Bellezza
,
A.
,
Thompson
,
H.
, and
Burgoyne
,
C. F.
,
2007
, “
Three-Dimensional Histomorphometry of the Normal and Early Glaucomatous Monkey Optic Nerve Head: Neural Canal and Subarachnoid Space Architecture
,”
Invest. Ophthalmol. Visual Sci.
,
48
(
7
), pp.
3195
3208
.10.1167/iovs.07-0021
17.
Grytz
,
R.
, and
Siegwart
,
J. T.
,
2015
, “
Changing Material Properties of the Tree Shrew Sclera During Minus Lens Compensation and Recovery
,”
Invest. Opthalmol. Visual Sci.
,
56
(
3
), p.
2065
.10.1167/iovs.14-15352
18.
Coudrillier
,
B.
,
Pijanka
,
J. K.
,
Jefferys
,
J. L.
,
Goel
,
A.
,
Quigley
,
H. A.
,
Boote
,
C.
, and
Nguyen
,
T. D.
,
2015
, “
Glaucoma-Related Changes in the Mechanical Properties and Collagen Micro-Architecture of the Human Sclera
,”
PLoS One
,
10
(
7
), p.
e0131396
.10.1371/journal.pone.0131396
19.
Girard
,
M. J. A.
,
Downs
,
J. C.
,
Bottlang
,
M.
,
Burgoyne
,
C. F.
, and
Suh
,
J.-K. F.
,
2009
, “
Peripapillary and Posterior Scleral Mechanics—Part II: Experimental and Inverse Finite Element Characterization
,”
ASME J. Biomech. Eng.
,
131
(
5
), p.
051012
.10.1115/1.3113683
20.
Boazak
,
E. M.
,
d'Humières
,
J.
,
Read
,
A. T.
, and
Ethier
,
C. R.
,
2019
, “
Compressive Mechanical Properties of Rat and Pig Optic Nerve Head
,”
ASME J. Biomech.
,
93
, pp.
204
208
.10.1016/j.jbiomech.2019.06.014
21.
Girard
,
M. J. A.
,
Downs
,
J. C.
,
Burgoyne
,
C. F.
, and
Suh
,
J.-K. F.
,
2009
, “
Peripapillary and Posterior Scleral Mechanics—Part I: Development of an Anisotropic Hyperelastic Constitutive Model
,”
ASME J. Biomech. Eng.
,
131
(
5
), p.
051011
.10.1115/1.3113682
22.
Maas
,
S. A.
,
Ellis
,
B. J.
,
Ateshian
,
G. A.
, and
Weiss
,
J. A.
,
2012
, “
FEBio: Finite Elements for Biomechanics
,”
ASME J. Biomech. Eng.
,
134
(
1
), p.
011005
.10.1115/1.4005694
23.
Coudrillier
,
B.
,
Pijanka
,
J.
,
Jefferys
,
J.
,
Sorensen
,
T.
,
Quigley
,
H. A.
,
Boote
,
C.
, and
Nguyen
,
T. D.
,
2015
, “
Collagen Structure and Mechanical Properties of the Human Sclera: Analysis for the Effects of Age
,”
ASME J. Biomech. Eng.
,
137
(
4
), p.
041006
.10.1115/1.4029430
24.
Grytz
,
R.
,
Fazio
,
M. A.
,
Girard
,
M. J. A.
,
Libertiaux
,
V.
,
Bruno
,
L.
,
Gardiner
,
S.
,
Girkin
,
C. A.
, and
Crawford Downs
,
J.
,
2014
, “
Material Properties of the Posterior Human Sclera
,”
J. Mech. Behav. Biomed. Mater.
,
29
, pp.
602
617
.10.1016/j.jmbbm.2013.03.027
25.
Baumann
,
B.
,
Rauscher
,
S.
,
Gl
,
M.
,
Erich
,
G.
,
Pircher
,
M.
,
Fialov
,
S.
,
Gr
,
M.
, and
Hitzenberger
,
C. K.
,
2014
, “
Peripapillary Rat Sclera Investigated In Vivo With Polarization-Sensitive Optical Coherence Tomography
,”
Invest. Ophthalmol. Visual Sci.
,
55
(
11
), pp.
7686
7696
.10.1167/iovs.14-15037
26.
Grytz
,
R.
, and
Downs
,
J. C.
,
2013
, “
A Forward Incremental Prestressing Method With Application to Inverse Parameter Estimations and Eye-Specific Simulations of Posterior Scleral Shells
,”
Comput. Methods Biomech. Biomed. Eng.
,
16
(
7
), pp.
768
780
.10.1080/10255842.2011.641119
27.
Pazos
,
M.
,
Yang
,
H.
,
Gardiner
,
S. K.
,
Cepurna
,
W. O.
,
Johnson
,
E. C.
,
Morrison
,
J. C.
, and
Burgoyne
,
C. F.
,
2016
, “
Expansions of the Neurovascular Scleral Canal and Contained Optic Nerve Occur Early in the Hypertonic Saline Rat Experimental Glaucoma Model
,”
Exp. Eye Res.
,
145
, pp.
173
186
.10.1016/j.exer.2015.10.014
28.
Jia
,
L.
,
Cepurna
,
W. O.
,
Johnson
,
E. C.
, and
Morrison
,
J. C.
,
2000
, “
Patterns of Intraocular Pressure Elevation After Aqueous Humor Outflow Obstruction in Rats
,”
Invest. Ophthalmol. Visual Sci.
,
41
(
6
), pp.
1380
1385
.https://iovs.arvojournals.org/article.aspx?articleid=2123102
29.
Tehrani
,
S.
,
Davis
,
L.
,
Cepurna
,
W. O.
,
Choe
,
T. E.
,
Lozano
,
D. C.
,
Monfared
,
A.
,
Cooper
,
L.
,
Cheng
,
J.
,
Johnson
,
E. C.
, and
Morrison
,
J. C.
,
2016
, “
Astrocyte Structural and Molecular Response to Elevated Intraocular Pressure Occurs Rapidly and Precedes Axonal Tubulin Rearrangement Within the Optic Nerve Head in a Rat Model
,”
PLoS One
,
11
(
11
), p.
e0167364
.10.1371/journal.pone.0167364
30.
Nguyen
,
C.
,
Midgett
,
D.
,
Kimball
,
E.
,
Jefferys
,
J.
,
Nguyen
,
T. D.
,
Schaub
,
J.
,
Pease
,
M.
, and
Quigley
,
H.
,
2018
, “
Age-Related Changes in Quantitative Strain of Mouse Astrocytic Lamina Cribrosa and Peripapillary Sclera Using Confocal Microscopy in an Explant Model
,”
Invest. Ophthalmol. Visual Sci.
,
59
(
12
), pp.
5157
5166
.10.1167/iovs.18-25111
31.
Nguyen
,
C.
,
Midgett
,
D.
,
Kimball
,
E. C.
,
Steinhart
,
M. R.
,
Nguyen
,
T. D.
,
Pease
,
M. E.
,
Oglesby
,
E. N.
,
Jefferys
,
J. L.
, and
Quigley
,
H. A.
,
2017
, “
Measuring Deformation in the Mouse Optic Nerve Head and Peripapillary Sclera
,”
Invest. Ophthalmol. Visual Sci.
,
58
(
2
), p.
721
.10.1167/iovs.16-20620
32.
Korneva
,
A.
,
Cone-Kimball
,
E.
,
Nguyen
,
T. D.
, and
Quigley
,
H. A.
,
2020
, “
Regional Mechanical Strains in Mouse Astrocytic Lamina and Peripapillary Sclera After Chronic IOP Elevation|IOVS|ARVO Journals
,”
ARVO
,
Baltimore, MD
.https://iovs.arvojournals.org/article.aspx?articleid=2770127
33.
Gogola
,
A.
,
Jan
,
N.
,
Lathrop
,
K. L.
, and
Sigal
,
I. A.
,
2018
, “
Radial and Circumferential Collagen Fibers Are a Feature of the Peripapillary Sclera of Human, Monkey, Pig, Cow, Goat, and Sheep
,”
Invest. Opthalmol. Visual Sci.
,
59
(
12
), p.
4763
.10.1167/iovs.18-25025
34.
Gouget
,
C. L. M.
,
Girard
,
M. J.
, and
Ethier
,
C. R.
,
2012
, “
A Constrained von Mises Distribution to Describe Fiber Organization in Thin Soft Tissues
,”
Biomech. Model. Mechanobiol.
,
11
(
3–4
), pp.
475
482
.10.1007/s10237-011-0326-y
35.
Girard
,
M. J. A.
,
Dahlmann-Noor
,
A.
,
Rayapureddi
,
S.
,
Bechara
,
J. A.
,
Bertin
,
B. M. E.
,
Jones
,
H.
,
Albon
,
J.
,
Khaw
,
P. T.
, and
Ethier
,
C. R.
,
2011
, “
Quantitative Mapping of Scleral Fiber Orientation in Normal Rat Eyes
,”
Invest. Ophthalmol. Visual Sci.
,
52
(
13
), pp.
9684
9693
.10.1167/iovs.11-7894
36.
Zhang
,
L.
,
Thakku
,
S. G.
,
Beotra
,
M. R.
,
Baskaran
,
M.
,
Aung
,
T.
,
Goh
,
J. C. H.
,
Strouthidis
,
N. G.
, and
Girard
,
M. J. A.
,
2017
, “
Verification of a Virtual Fields Method to Extract the Mechanical Properties of Human Optic Nerve Head Tissues In Vivo
,”
Biomech. Model. Mechanobiol.
,
16
(
3
), pp.
871
887
.10.1007/s10237-016-0858-2
37.
Schwaner
,
S. A.
,
Feola
,
A. J.
, and
Ethier
,
C. R.
,
2020
, “
Factors Affecting Optic Nerve Head Biomechanics in a Rat Model of Glaucoma
,”
J. R. Soc. Interface
,
17
(
165
).10.1098/rsif.2019.0695
38.
Fortune
,
B.
,
Choe
,
T. E.
,
Reynaud
,
J.
,
Hardin
,
C.
,
Cull
,
G. A.
,
Burgoyne
,
C. F.
, and
Wang
,
L.
,
2011
, “
Deformation of the Rodent Optic Nerve Head and Peripapillary Structures During Acute Intraocular Pressure Elevation
,”
Invest. Ophthalmol. Visual Sci.
,
52
(
9
), pp.
6651
6661
.10.1167/iovs.11-7578
39.
Lozano
,
D. C.
, and
Twa
,
M. D.
,
2013
, “
Development of a Rat Schematic Eye From In Vivo Biometry and the Correction of Lateral Magnification in SD-OCT Imaging
,”
Invest. Ophthalmol. Visual Sci.
,
54
(
9
), pp.
6446
6455
.10.1167/iovs.13-12575
40.
Kuo
,
A. N.
,
McNabb
,
R. P.
,
Chiu
,
S. J.
,
El-Dairi
,
M. A.
,
Farsiu
,
S.
,
Toth
,
C. A.
, and
Izatt
,
J. A.
,
2013
, “
Correction of Ocular Shape in Retinal Optical Coherence Tomography and Effect on Current Clinical Measures
,”
Am. J. Ophthalmol.
,
156
(
2
), pp.
304
311
.10.1016/j.ajo.2013.03.012
41.
Ling
,
Y. T. T.
,
Pease
,
M. E.
,
Quigley
,
H. A.
, and
Nguyen
,
T. D.
,
2020
, “
Actin and GFAP Network of Mouse Optic Nerve Head and Alterations With IOP|IOVS|ARVO Journals
,”
ARVO
,
Baltimore, MD
.https://iovs.arvojournals.org/article.aspx?articleid=2769975
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