Corneal Neovascularization
Introduction
Section titled “Introduction”Background
Section titled “Background”Corneal neovascularization is a pathological condition characterized by the abnormal growth of new blood vessels into the cornea, the transparent outermost layer of the eye. The cornea is naturally avascular (lacking blood vessels) to maintain its clarity, which is essential for proper vision. The presence of blood vessels disrupts this transparency, leading to visual impairment.
Biological Basis
Section titled “Biological Basis”The development of corneal neovascularization typically results from an imbalance between pro-angiogenic (blood vessel promoting) and anti-angiogenic (blood vessel inhibiting) factors. Under normal conditions, the cornea maintains a delicate balance favoring anti-angiogenic factors. However, various insults such as trauma, infection, inflammation, hypoxia, or certain corneal diseases can tip this balance. These conditions stimulate the release of pro-angiogenic factors, leading to the invasion of new vessels from the limbus (the corneal periphery) into the normally clear corneal stroma. Processes like corneal wound healing and the activity of resident immune cells in the cornea can be involved in initiating or modulating these responses.[1] The structural integrity of the cornea, heavily reliant on collagen and extracellular matrix (ECM) components [2] can also be compromised, further facilitating vessel ingrowth.
Clinical Relevance
Section titled “Clinical Relevance”Corneal neovascularization is a significant clinical concern due to its direct impact on vision. The ingrowing blood vessels can cause corneal opacity, lipid deposition, and scarring, all of which reduce corneal transparency and lead to decreased visual acuity. It complicates various eye surgeries, particularly corneal transplantation, as the presence of vessels increases the risk of graft rejection. Early detection and management are crucial to prevent progressive vision loss and preserve corneal health.
Social Importance
Section titled “Social Importance”From a societal perspective, corneal neovascularization represents a considerable public health burden. It can severely affect an individual’s quality of life, leading to challenges in daily activities, employment, and overall well-being. The costs associated with diagnosis, medical treatments, and potential surgical interventions place an economic strain on healthcare systems and affected individuals. Understanding its underlying genetic and biological mechanisms is vital for developing more effective preventative strategies and therapies, ultimately improving patient outcomes and reducing the social and economic impact of this sight-threatening condition.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Genetic studies of complex ocular traits frequently encounter limitations related to their design and statistical power. A primary concern is the need for exceptionally large sample sizes to detect the small effect sizes characteristic of individual genetic variants, with studies continuously expanding cohorts to uncover more loci. [3]While meta-analyses significantly boost power, they may also contribute to effect-size inflation for initially identified associations, and the absence of consistent replication across diverse populations can highlight underlying methodological issues or population-specific genetic architectures.[4] Further, varying approaches to handle related individuals or stratify analyses by age across cohorts [5] can complicate the synthesis of findings and comprehensive interpretation of genetic influences.
Specific cohort characteristics also introduce constraints; for example, the exclusion of individuals with ocular pathologies or prior surgeries [6]ensures a cleaner phenotype but restricts the generalizability of findings to the broader population. Such exclusions, while essential for minimizing confounding, mean the identified genetic factors may not fully capture the genetic landscape of a disease or trait in individuals with pre-existing conditions. These design choices collectively influence the power, precision, and ultimate applicability of genetic discoveries.
Generalizability and Phenotype Definition
Section titled “Generalizability and Phenotype Definition”The generalizability of findings in ocular genetic research is often limited by the ancestral composition of study populations. Many large-scale genetic studies predominantly feature individuals of European descent, despite efforts to include multiethnic cohorts. [7] This imbalance means that genetic architecture and allele frequencies may not be accurately captured or directly transferable to other populations, as demonstrated by differences in imputation panel effectiveness across ancestries. [4] Discrepancies in SNP-heritability estimates between European and Asian populations [5] further underscore the existence of population-specific genetic influences, making it crucial for future research to broaden ancestral diversity to ensure global applicability.
Accurate and consistent phenotyping also presents a notable challenge. Ocular traits can be subject to variability in measurement techniques and instrumentation; for instance, different models of biometers or pachymeters are used across studies. [7] While stringent quality control, such as requiring multiple consistent measurements or excluding extreme outliers, is routinely applied [5] subtle differences in measurement protocols or in defining trait thresholds can introduce heterogeneity and impact the comparability and reliability of findings across different research groups. These challenges necessitate careful harmonization of methods for more robust meta-analyses.
Unaccounted Confounders and Knowledge Gaps
Section titled “Unaccounted Confounders and Knowledge Gaps”A persistent limitation in dissecting the genetics of complex ocular traits stems from the influence of unmeasured environmental factors and intricate gene-environment interactions. While essential covariates like age, sex, and ancestry principal components are routinely adjusted for [7] the myriad of other environmental influences that could affect trait expression are often difficult to capture and model comprehensively. This incomplete accounting contributes to the phenomenon of “missing heritability,” where the currently identified genetic variants explain only a fraction of the total observed phenotypic variance [8] suggesting that a significant portion of both genetic and environmental contributions remains to be discovered.
Despite the identification of numerous genetic loci, considerable knowledge gaps remain concerning the precise biological mechanisms underlying these associations. While studies may converge on general biological pathways, such as those related to collagen and extracellular matrix [3] the detailed molecular and cellular processes by which specific genetic variants impact ocular structure and function are often not fully elucidated. Addressing these gaps requires further functional validation studies, deeper exploration of rare variants, and integrated analyses to fully understand the etiological complexities of these traits.
Variants
Section titled “Variants”Genetic variations play a crucial role in regulating fundamental cellular processes that contribute to the development and maintenance of corneal health, influencing conditions such as corneal neovascularization. Genes involved in cell signaling, metabolism, and differentiation are particularly relevant to this complex process. For instance,STK11 (rs183640372 ), a serine/threonine kinase, acts as a master regulator of cell polarity and metabolism, influencing pathways critical for cell growth and proliferation. Variants inSTK11could alter these regulatory mechanisms, potentially impacting the aberrant cellular proliferation seen in corneal neovascularization. Similarly,ADCY2 (rs184421129 ) encodes adenylate cyclase, an enzyme that produces cyclic AMP (cAMP), a vital second messenger involved in numerous signal transduction pathways that regulate cell growth and development. [9] Dysregulation of cAMP signaling by variants in ADCY2 could contribute to the uncontrolled cell expansion characteristic of new blood vessel formation in the cornea. [10]
Further impacting cellular activity, PDE1C (rs571008725 ) encodes a phosphodiesterase that hydrolyzes cyclic nucleotides like cAMP and cGMP, thereby controlling their intracellular levels. Alterations caused by variants in PDE1Ccould lead to imbalances in these critical signaling molecules, affecting processes such as cell migration, proliferation, and inflammation—all pertinent to the development of corneal neovascularization. The transcription factorKLF17 (rs189464266 ) is involved in regulating cell proliferation, differentiation, and programmed cell death. Genetic changes in KLF17 may modify its transcriptional activity, potentially influencing corneal cellular responses and contributing to or protecting against pathological changes in corneal tissue. [11]These intricate signaling and regulatory elements are fundamental to maintaining corneal transparency and preventing unwanted vascular invasion, emphasizing the need for understanding the “molecular mechanism of cornea-related disease”.[12]
Beyond core regulatory pathways, genes involved in stem cell biology, apoptosis, and immune responses also exert significant influence. MSI2 (rs796256065 ) encodes an RNA-binding protein important for maintaining stem cell properties and regulating mRNA translation, which is crucial for corneal epithelial stem cell function and regeneration. Variants in MSI2 could impair corneal regeneration or promote abnormal cell survival, indirectly supporting neovascularization. PID1 (rs184644914 ) plays a role in cell differentiation and apoptosis, processes that are fundamental for removing unwanted cells and maintaining tissue homeostasis. [10] An altered function of PID1 due to rs184644914 could lead to dysregulated cell turnover, a factor in various corneal disorders. Moreover, IL17RE (rs745494800 ) encodes a receptor for interleukin-17 cytokines, key mediators of inflammatory and immune responses. Variants in IL17RE may modify the corneal inflammatory environment, potentially exacerbating angiogenesis by influencing “vascular endothelial cells” .
Finally, genes linked to metabolism and broader ocular development contribute to the intricate network affecting corneal health. The TMEM74 - TRHR locus, encompassing variants like rs185560321 , could influence cellular autophagy through TMEM74, a process vital for cellular stress response and survival, or affect neuroendocrine signaling through TRHR, potentially impacting corneal innervation and wound healing. Retinoid metabolism is critical for eye development and can influence angiogenesis; thus, variants at the NT5C1B - RDH14 locus, such as rs922468689 , particularly those impacting RDH14, could modulate the local retinoid environment in the cornea. This could either promote or inhibit the growth of new blood vessels, making these genes relevant to overall “ocular growth/development”. [13] The combined effects of these genetic variations highlight the complex interplay of cellular functions and environmental responses that dictate corneal integrity and vulnerability to neovascularization, leading to “cornea-related phenotypes”. [9]
Key Variants
Section titled “Key Variants”Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Causes of Corneal Neovascularization
Section titled “Causes of Corneal Neovascularization”Corneal neovascularization, the pathological ingrowth of new blood vessels into the normally avascular cornea, is a complex condition driven by an interplay of genetic predispositions, disruptions in molecular pathways, developmental factors, and associated ocular diseases. Research indicates that the cornea’s structural integrity, cellular homeostasis, and immune privilege are influenced by numerous factors, which, when compromised, can lead to the initiation and progression of neovascularization.
Genetic Factors Affecting Corneal Structure and Biomechanics
Section titled “Genetic Factors Affecting Corneal Structure and Biomechanics”Genetic variants significantly influence the inherent structure and biomechanical properties of the cornea, predisposing it to conditions that can trigger neovascularization. Genome-wide association studies (GWAS) have identified numerous loci associated with critical corneal characteristics. For instance, gene-set enrichment analyses highlight a strong association with collagen pathways, essential for the cornea’s extracellular matrix (ECM) and structural strength. [2] Genetic variants influencing central corneal thickness (CCT), such as those near WNT7B or other CCT-associated loci, are linked to collagen and ECM pathways, underscoring the genetic basis of corneal biomechanics. [5] Disruptions in these fundamental structural components can lead to corneal weakening, altered biomechanical properties, or damage, thereby potentially initiating inflammatory responses and subsequent neovascularization as the body attempts repair.
Genetic factors also influence critical corneal cell populations and signaling. Sequence variation at ANAPC1, for example, accounts for a significant portion of the variability in corneal endothelial cell density, which is crucial for maintaining corneal clarity. [8]Compromised endothelial function can lead to edema and overall corneal dysfunction, potentially triggering reparative processes that include new vessel growth. Furthermore, multiple independent causal signals have been identified at numerous loci for corneal traits, indicating a polygenic architecture where many variants, like those within the platelet-derived growth factor receptor alpha (PDGFRA) locus influencing corneal curvature, contribute to susceptibility. [14] The PDGFRA gene family plays a known role in angiogenesis, suggesting a more direct genetic link to pathways involved in neovascularization.
Molecular Pathways and Cellular Homeostasis Disruptions
Section titled “Molecular Pathways and Cellular Homeostasis Disruptions”The disruption of molecular pathways crucial for corneal homeostasis and immune regulation significantly contributes to pathologies that can lead to neovascularization. For example, a novel locus associated with Fuchs endothelial corneal dystrophy (FECD) near HS3ST3B1 highlights the importance of heparan sulfate (HS) in corneal health, as HS is critical for maintaining corneal epithelial homeostasis. [1]Loss of corneal epithelial HS can lead to corneal degeneration and impaired wound healing[15] while heparanase overexpression, which degrades HS, is correlated with keratoconus severity. [16]Such compromised healing and degeneration can induce sustained inflammatory signals, which are potent drivers of corneal neovascularization.
Genetic variants also impact corneal immune responses and cell-specific functions. The FECD index single nucleotide polymorphism (SNP) atRORA, for instance, is linked to keratoconus risk and regulates type-2 innate lymphoid cells, a resident immune cell population in the cornea. [1] Dysregulated immune responses and chronic inflammation are well-established precursors to neovascularization. Conditions like FECD and keratoconus, characterized by endothelial cell dysfunction or stromal weakening, respectively, show overlapping genetic risk loci and often involve altered cell-to-cell contact and tissue integrity, which can contribute to a pro-angiogenic environment within the cornea. [14]
Developmental and Systemic Influences
Section titled “Developmental and Systemic Influences”Beyond direct corneal genes, genetic enrichment analyses indicate links to broader systemic developmental pathways, such as “Skeletal System Development”. [2] This suggests that some underlying genetic predispositions affecting corneal properties may stem from general developmental programs, influencing the initial formation and long-term health of ocular tissues. Early life influences, potentially related to genetic variants disrupting normal eye development—for instance, by affecting cell cycle regulation as seen with an ANAPC1 homologue—could create a cornea inherently more susceptible to injury, inflammation, and the angiogenic responses that characterize neovascularization. [17]
Associated Ocular Conditions and Age-Related Changes
Section titled “Associated Ocular Conditions and Age-Related Changes”Corneal neovascularization frequently arises as a complication of various pre-existing ocular conditions that compromise corneal health. Studies identifying shared genetic influences across central corneal thickness, keratoconus, and Fuchs endothelial corneal dystrophy (FECD) highlight a common genetic etiology for these complex eye diseases.[3] These conditions, characterized by stromal thinning, endothelial dysfunction, or biomechanical alterations, can lead to chronic irritation, inflammation, or structural damage that strongly predisposes the cornea to pathological vascular invasion. Furthermore, age-related changes, such as increased ocular tissue stiffness, may also contribute to the progression of corneal diseases and affect the cornea’s ability to withstand insults, thereby increasing the risk of subsequent neovascularization. [18]
Biological Background
Section titled “Biological Background”Animal Model Evidence
Section titled “Animal Model Evidence”Investigating Corneal Extracellular Matrix and Structural Components
Section titled “Investigating Corneal Extracellular Matrix and Structural Components”Animal models have been instrumental in elucidating the complex interplay of extracellular matrix (ECM) components that maintain corneal structural integrity, offering insights relevant to various corneal conditions. Genetic manipulation studies in mice have revealed the critical roles of specific collagens in corneal development and maturation. For example, collagen XII and collagen XIV null mice exhibit abnormal corneal endothelial maturation, demonstrating the necessity of these collagens for proper endothelial development. [9] Similarly, research in zebrafish utilizing knockdown approaches for the lumican gene (zlum) has shown that its deficiency can lead to scleral thinning and increased size of scleral coats, underscoring the broader ocular structural importance of small leucine-rich proteoglycans like lumican.[9]These studies provide foundational understanding of gene functions and disease mechanisms underlying corneal structural disorders, offering potential targets for therapeutic intervention.
Exploring Growth Factor and Cellular Signaling Pathways in Corneal Biology
Section titled “Exploring Growth Factor and Cellular Signaling Pathways in Corneal Biology”Diverse animal models contribute to understanding the intricate growth factor and cellular signaling pathways that govern corneal homeostasis and responses to injury. Although the specific models were not detailed, pathways such as IGF-1 signaling, neuregulin signaling, NGF signaling, and the ErbB signaling pathway have been reported to exert biological effects in human corneas, regulating cell proliferation, differentiation, and migration. [10] Similarly, the Wnt/beta-catenin signaling pathway, notably through WNT7B, is recognized for its role in regulating the proliferation of human corneal epithelial stem/progenitor cells and promoting cell proliferation and matrix metalloproteinase-12 expression during corneal wound healing. [10] These insights into key signaling cascades are typically derived or validated through experimental animal models, highlighting critical pathways that could be modulated for therapeutic purposes in corneal pathologies.
Role of Proteoglycans and Collagen in Corneal Development and Disease
Section titled “Role of Proteoglycans and Collagen in Corneal Development and Disease”Animal models further illuminate the contributions of proteoglycans and collagen to corneal development, biomechanics, and disease. Genome-wide association studies (GWAS) have identified strong enrichment for collagen pathways and proteinaceous ECM pathways in association with central corneal thickness and biomechanical properties[3]. [2] Genes like DCN (decorin) and LUM (lumican) are highly expressed in the human cornea, with decorin mutations linked to congenital stromal dystrophy. [9]Functional studies often employ animal models to dissect how disruptions in these ECM components and proteoglycans lead to structural abnormalities, providing a platform to validate gene functions and test interventions aimed at restoring corneal integrity. These models are crucial for translating genetic findings into a deeper understanding of human corneal biology and disease.
Frequently Asked Questions About Corneal Neovascularization
Section titled “Frequently Asked Questions About Corneal Neovascularization”These questions address the most important and specific aspects of corneal neovascularization based on current genetic research.
1. My parents have eye issues. Am I more likely to get blood vessels in my cornea?
Section titled “1. My parents have eye issues. Am I more likely to get blood vessels in my cornea?”Yes, your genetics can influence how healthy and resilient your cornea is. Inherited variations in genes that affect corneal structure, like those involved in collagen and extracellular matrix components, can predispose you to weaker corneal traits. If your family has these predispositions, your cornea might be more susceptible to the damage or inflammation that triggers new blood vessel growth.
2. Does my ethnic background change my risk of this eye problem?
Section titled “2. Does my ethnic background change my risk of this eye problem?”Yes, genetic influences on corneal characteristics can differ significantly across various ancestral groups. Research indicates that the genetic factors and their frequencies can vary between populations. This means your ethnic background might have a unique set of genetic predispositions that could affect your cornea’s health and its susceptibility to conditions like neovascularization.
3. Why do some people never get this, even with eye injuries?
Section titled “3. Why do some people never get this, even with eye injuries?”Your individual genetic makeup plays a key role in your cornea’s natural defenses and ability to heal. Some people may have genetic variations that contribute to a more robust corneal structure or a balanced immune response, making them naturally more resistant to blood vessel formation even after trauma. Others might have variations that make them more prone to an inflammatory response that encourages vessel growth.
4. If I have a strong family history, can I still prevent it?
Section titled “4. If I have a strong family history, can I still prevent it?”While genetics can create a predisposition, environmental factors and lifestyle choices are extremely important. Actively protecting your eyes from injury, managing infections promptly, and controlling inflammation can significantly reduce the triggers for neovascularization. Early detection and treatment of any underlying corneal conditions are crucial steps you can take, regardless of your genetic background.
5. Should I get a genetic test to see my risk for this?
Section titled “5. Should I get a genetic test to see my risk for this?”Currently, there isn’t a single, widely available genetic test specifically for predicting corneal neovascularization risk. However, genetic studies are identifying many genes related to overall corneal health, such as those affecting corneal thickness or biomechanical strength. As research advances, comprehensive genetic tests for broader ocular health assessment, which could indirectly relate to neovascularization risk, may become more common.
6. Does my daily screen time affect my genetic risk of vessel growth?
Section titled “6. Does my daily screen time affect my genetic risk of vessel growth?”Direct genetic risk for corneal neovascularization isn’t typically altered by screen time itself. However, prolonged screen use can contribute to eye strain, dry eyes, or irritation, potentially leading to local inflammation. If you have a genetic predisposition to corneal issues, any increased inflammation could act as an environmental trigger that encourages blood vessel formation.
7. Can what I eat or how much I exercise impact my cornea’s genes?
Section titled “7. Can what I eat or how much I exercise impact my cornea’s genes?”Your diet and exercise habits don’t change your underlying genes, but they profoundly influence your body’s overall health and inflammatory state. A balanced diet and regular exercise can help maintain general ocular health and reduce systemic inflammation. This can mitigate environmental triggers for corneal damage that might lead to neovascularization, especially if you have a genetic susceptibility.
8. I heard aging makes eyes weaker. Does genetics play a part here?
Section titled “8. I heard aging makes eyes weaker. Does genetics play a part here?”Yes, genetics significantly influences how your cornea ages and maintains its strength over time. Variations in genes related to structural components like collagen and extracellular matrix, or those affecting the health and density of corneal endothelial cells, can determine your cornea’s resilience. These genetic factors impact its susceptibility to weakening and conditions like neovascularization as you grow older.
9. If I get an eye infection, am I genetically more likely to get blood vessels?
Section titled “9. If I get an eye infection, am I genetically more likely to get blood vessels?”An eye infection is a potent trigger for corneal neovascularization. Your genetic makeup influences your immune system’s response to infection and how your cornea heals. Some people may have genetic predispositions that cause their cornea to react more intensely to pathogens, increasing the likelihood of vessel formation as part of an exaggerated wound healing or inflammatory process.
10. Why would my doctor consider my genetics before eye surgery?
Section titled “10. Why would my doctor consider my genetics before eye surgery?”While not always specific to neovascularization risk, understanding your genetic background for general corneal traits is increasingly valuable. For example, genetic factors influencing corneal thickness or biomechanical properties can help assess overall corneal health and predict surgical outcomes. This information can guide decisions and help manage risks, especially since existing blood vessels are known to complicate surgeries like corneal transplantation by increasing the risk of graft rejection.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Gorman, B. R. et al. “A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation.” Communications Biology, vol. 7, no. 1, 2024, p. 385.
[2] Simcoe, M. J. et al. “Genome-wide association study of corneal biomechanical properties identifies over 200 loci providing insight into the genetic aetiology of ocular diseases.” Hum Mol Genet, vol. 29, no. 19, 2020, pp. 3290–3303, PMID: 32716492.
[3] Lu, Y. et al. “Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus.” Nat Genet, 2013.
[4] Bonnemaijer, P. W. M. et al. “Multi-trait genome-wide association study identifies new loci associated with optic disc parameters.” Commun Biol, vol. 2, 2019, p. 435, PMID: 31798171.
[5] Fan, B. J. et al. “Family-Based Genome-Wide Association Study of South Indian Pedigrees Supports WNT7B as a Central Corneal Thickness Locus.” Invest Ophthalmol Vis Sci, vol. 59, 2018, pp. 2970–2975, PMID: 29847655.
[6] Shah, R. L. et al. “A genome-wide association study of corneal astigmatism: The CREAM Consortium.” Mol Vis, vol. 25, 2019, pp. 64–74, PMID: 29422769.
[7] Choquet, H. et al. “A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness.” Nature Communications, vol. 8, no. 1, 2017, p. 14713.
[8] Ivarsdottir, E. V. et al. “Sequence variation at ANAPC1 accounts for 24% of the variability in corneal endothelial cell density.” Nat Commun, vol. 10, 2019, p. 1284, PMID: 30894546.
[9] Iglesias, A. I. et al. “Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.” Nat Commun, vol. 9, 2018, p. 2064, PMID: 29760442.
[10] Gao, X. et al. Genome-wide association study identifies WNT7B as a novel locus for central corneal thickness in Latinos. Hum Mol Genet, 2017.
[11] Afshari, N. A. et al. “Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy.” Nature Communications, vol. 8, no. 1, 2017, p. 14713.
[12] Yazar, S. “Interrogation of the platelet-derived growth factor receptor alpha locus and corneal astigmatism in Australians of Northern European ancestry: results of a genome-wide association study.” Mol Vis, 2013.
[13] Fan, Q. et al. “Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.” Commun Biol, 2020.
[14] Jiang, X. et al. “Fine-mapping and cell-specific enrichment at corneal resistance factor loci prioritize candidate causal regulatory variants.”Commun Biol, 2020, PMID: 33311554.
[15] Coulson-Thomas, V. J. et al. “Loss of corneal epithelial heparan sulfate leads to corneal degeneration and impaired wound healing.”Investigative Ophthalmology & Visual Science, vol. 56, no. 5, 2015, pp. 3004-3014.
[16] García, B. et al. “Heparanase overexpresses in keratoconic cornea and tears depending on the pathologic grade.” Disease Markers, vol. 2017, 2017, p. 3502386.
[17] Gusev, F. P. et al. “An ANAPC1 homologue shattered disrupts normal eye development by disrupting G1 cell cycle arrest and progression through mitosis.” Developmental Biology, vol. 309, no. 2, 2007, pp. 222-235.
[18] Liu, B. et al. “Aging and ocular tissue stiffness in glaucoma.”Survey of Ophthalmology, vol. 63, no. 1, 2018, pp. 56-74.