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antioxidantsReview
Vitreous Antioxidants, Degeneration,
and Vitreo-Retinopathy: Exploring the Links
Emmanuel Ankamah 1,2, * , J. Sebag 3 , Eugene Ng 1,2 and John M. Nolan 1, *
1 Nutrition Research Centre Ireland, School of Health Science, Carriganore House, Waterford Institute of
Technology, West Campus, Co., X91 K236 Waterford, Ireland; eugene@ioes.ie
2 Institute of Eye Surgery, UPMC Whitfield, Buttlerstown, Co., X91 DH9W Waterford, Ireland
3 VMR Consulting Inc., Huntington Beach, CA 92647, USA; JSebag@vmrinstitute.com
* Correspondence: emmanuel.ankamah@postgrad.wit.ie (E.A.); jmnolan@wit.ie (J.M.N.)
Received: 26 November 2019; Accepted: 16 December 2019; Published: 20 December 2019
Abstract: The transparent vitreous body, which occupies about 80% of the eye’s volume, is laden
with numerous enzymatic and non-enzymatic antioxidants that could protect the eye from oxidative
stress and disease. Aging is associated with degeneration of vitreous structure as well as a
reduction in its antioxidant capacity. A growing body of evidence suggests these age-related
changes may be the precursor of numerous oxidative stress-induced vitreo-retinopathies, including
vision degrading myodesopsia, the clinically significant entoptic phenomena that can result from
advanced vitreous degeneration. Adequate intravitreal antioxidant levels may be protective against
vitreous degeneration, possibly preventing and even improving vision degrading myodesopsia as
well as mitigating various other vitreo-retinopathies. The present article is, therefore, a review of
the different antioxidant molecules within vitreous and the inter-relationships between vitreous
antioxidant capacity and degeneration.
Keywords: antioxidants; vitreous; oxidative stress; vitreous degeneration; floaters; vision
degrading myodesopsia
1. Introduction
Ocular Antioxidants—Protection against Oxidative Damage and Disease
Vision relies on the coordinated roles played by various structures of the visual system, from the
tear film on the ocular surface to the visual centers within the brain. Visual perception commences with
sensory information organization, the process by which the highly specialized neurosensory retina of the
eye captures photons from the environment and converts them into neural signals for visual processing
and transmission to the higher visual centers within the brain [1]. Concurrently, the eye is exposed to
exogenous, potentially injury-precipitating factors including visible light, ultraviolet light, ionizing
radiation, and environmental toxins; as well as endogenous stress-inducing influences generated by
the mitochondria within ocular tissues during the eye’s physiological functions [2]. These endogenous
and exogenous oxidants produce unstable reactive oxygen species (ROS) characterized by one or two
unpaired electrons within their external orbit [3].
While normal concentrations of ROS are a physiological response to stress and are an integral
part of normal ocular metabolic activity, excess levels could be debilitating to the eye [4]. To remain
functional, the eye is replete with an assortment of antioxidants (substances that, when present in low
concentrations compared to that of an oxidizable substrate, significantly delay or inhibit the oxidation
of the substrate) by which it mitigates the damaging effects of ROS [5]. Over-production or inadequate
elimination of ROS beyond the counteracting ability of the eye’s antioxidant system can cause ocular
Antioxidants 2020, 9, 7; doi:10.3390/antiox9010007 www.mdpi.com/journal/antioxidants
,Antioxidants 2020, 9, 7 2 of 20
tissues to be overwhelmed, a phenomenon referred to as oxidative stress [6]. The pathological cascade
following oxidative stress are ocular physiologic dysfunction, ocular tissue death and consequently,
ocular degenerative disorders [7].
Emerging evidence suggests a relationship between decreased intraocular antioxidant capacity
and the onset of ocular diseases such as endothelial Fuch’s dystrophy, cataract, age-related macular
degeneration (AMD), and diabetic retinopathy (DR) [2,8,9]. Also, aging, toxins, inflammations,
infections, and possibly nutritional imbalance deplete intraocular antioxidants, necessitating a constant
supply of antioxidants via diet or supplementation [10]. It is thus not surprising to observe recent
strides in research focused on the application of antioxidants as plausible therapeutic and prophylactic
agents in the management of ocular diseases, an idea which forms a critical aspect of personalized
medicine and an important future direction in healthcare [11,12].
Conventional medicine, as has been practiced over the years, is a disease-oriented and reactive
approach of treating patients’ complaints as well as ensuring that clinically measured disease-related
indices are normalized. This approach of “disease care” appropriates the majority of health resources
to the management of clinical manifestation of severe pathologies, and fails to address the entirety of
health, which is a state of complete physical, mental and social well-being, and not just the absence of
disease [13,14].
Personalized medicine, a predictive, preventive, and individual-specific approach to healthcare,
on the other hand, focusses on identifying distinct profiles of a person’s health: genetic, biological,
and environmental, with the ultimate goal of either avoiding the manifestation of diseases in individuals
or providing treatments customized to the person in question [15]. Facilitated by the constant
innovations in biochemical, genomic, and diagnostic apparatus, the trajectory towards personalized
medicine will involve everything ranging from lifestyle modifications (physical exercise and dietary
or nutritional prescriptions), health promotion campaigns, screening exercises, predictive algorithms
to isolate individuals with high risk of disease, telemedicine monitoring and assessment, early and
appropriate diagnosis, to genetic-tailored therapies for diseases. Not only will this preventive and
specific healthcare delivery improve patient well-being but also reduce the financial burden on patients
and healthcare systems [16]. Thus, dietary supplementation with antioxidants, aimed at mitigating
oxidative stress and injury, may subserve the preventive aspects of personalized medicine, including
eye care.
Antioxidant molecules within some ocular structures namely aqueous humour, cornea, crystalline
lens, and retina have been reviewed elsewhere [2,17]. However, there is little information on the
antioxidant profile of the vitreous body [2,18]. The present review therefore examines the various
antioxidant molecules within vitreous and how their depletion might influence vitreous degeneration
and the pathogenesis of vitreo-retinal diseases. Evidence from reviews, metabolomic, and proteomic
studies of vitreous was examined, and the identified vitreous antioxidant molecules will be discussed.
2. The Vitreous Body
A Look at the Vitreous Body and Not just through It
Historically, vitreous was noted mainly for its contribution to intraocular clarity and to the
maintenance of the globe’s shape. As a result, no physiological importance was ascribed to vitreous,
further fueled by decades of experience in surgically removing vitreous without apparent detriment
to ocular health [19,20]. However, enabled by advancements in vitreous imaging and biochemical
analyses, recent studies have provided invaluable insights into the molecular constitution of this
seemingly invisible organ, and its contribution to ocular health and disease [21,22]. Thus, it has become
imperative for eye care professionals to critically observe vitreous while examining their patients and
for scientists to consolidate efforts at enhancing our understanding of vitreous in healthy and diseased
states. The current disposition is succinctly captured in a quote by Prof. J. Sebag who admonishes to
“look at vitreous and not just through it [21].”
, and its removal in vitro results in vitreous liquefaction [19,35]. Hyaluronan, a polydisperse
polysaccharide, is the predominant GAG within vitreous [36]. The concentration of HA within
vitreous ranges between 0.02–1 mg/cm3 [37]. As the primary mediator of the internal adhesivity of
vitreous, HA plays a synergistic role with collagen and other proteoglycans in regulating the stiffness
of vitreous
Antioxidants 2020,[38].
9, 7 3 of 20
As a connective tissue matrix, vitreous shares similar biochemical properties with the synovial
tissue around joint spaces. Both vitreous and synovial fluid are viscoelastic tissues consisting mainly
A look at the vitreous body reveals that it is the largest ocular structure filling the space within
of collagen and HA. Vitreous collagen type II, however, differs slightly in chemical composition due
the posterior segment bordered by the posterior lens surface and the inner limiting membrane (ILM)
to the presence of terminal peptide constituents in its collagen [39]. Particular to vitreous and cartilage
of the retina. With a total volume of approximately 4 mL, the vitreous body is mainly composed of
is an acidic glycoprotein with a five-armed configuration, cartilage oligomeric matrix protein [40]. Its
water (about 98%–99%), collagen fibres, glycosaminoglycans (GAGs; predominantly hyaluronan),
function in vitreous is, however, yet to be identified. Vitreous and synovial fluid separate tissues and
non-collagenous proteins (including opticin and versican), and small amounts of trace metals and
protect against friction and high-frequency stresses [41]. The similarities in macromolecular structure
elements [23,24]. The gel nature of vitreous is attributed to the interaction between its two principal
between vitreous and joints is the underlying explanation as to why both tissues show characteristic
components, collagen and hyaluronan (Figure 1).
clinical manifestations in inherited collagen disorders such as Marfan and Ehlers–Danlos syndromes.
Figure Cross-sectional
1. 1.
Figure diagram
Cross-sectional ofof
diagram thethe
human
humaneye showing
eye thethe
showing vitreous body
vitreous and
body thethe
and interaction
interaction
between its two principal components, collagen and hyaluronan. Courtesy of Emmanuel Ankamah.
between its two principal components, collagen and hyaluronan. Courtesy of Emmanuel Ankamah.
The vitreous body is subdivided into 3 broad anatomical regions: vitreous cortex (anterior and
posterior), central vitreous, and vitreous base. The vitreous cortex is a lamellar structure attached to
the ILM of the retina posterior to the peripheral vitreous base by an extracellular matrix “adhesive”
consisting of fibronectin, opticin, laminin, heparan sulfate, and chondroitin sulphate. Anteriorly, the
vitreous cortex is attached to the lens [25]. Vitreous is relatively acellular with only a monolayer of
mononuclear phagocytes, hyalocytes, located within the posterior vitreous cortex, about 50 µM from
the ILM [26]. Vitreous contributes to intraocular media clarity, the regulation of intraocular oxygen
tension, and the maintenance of intraocular pressure [27]. It also confers protection by acting as a
shock absorber, done by the collagen fibres which reduce the compressive forces of hyaluronan (HA)
when the globe is exposed to external pressure [28,29]. Vitreous acts as a reservoir for nutrients and
metabolites that it receives from synthesis within the non-pigmented ciliary epithelium and retinal
pigment epithelium [19,30–32]. Hyalocytes play a vital role in modulating intraocular inflammation in
non-inflamed eyes, thereby contributing to intraocular transparency [26].
Collagen concentration within the human vitreous body approximates to 300 µg/mL, accounting
for 0.5% of the total vitreous protein [33]. Vitreous assembles collagen fibres in a heterotypic fashion,
organizing collagen types II, V/XI, VI, and IX, with collagen II being the most abundant. Vitreous
collagen fibrils are thin and unbranched with uniform diameter ranging between 10 to 20 nm (depending
on the species) [34]. Collagen constitutes the essential structural component of vitreous and its removal
in vitro results in vitreous liquefaction [19,35]. Hyaluronan, a polydisperse polysaccharide, is the
predominant GAG within vitreous [36]. The concentration of HA within vitreous ranges between
0.02–1 mg/cm3 [37]. As the primary mediator of the internal adhesivity of vitreous, HA plays a
synergistic role with collagen and other proteoglycans in regulating the stiffness of vitreous [38].
As a connective tissue matrix, vitreous shares similar biochemical properties with the synovial
tissue around joint spaces. Both vitreous and synovial fluid are viscoelastic tissues consisting mainly of
collagen and HA. Vitreous collagen type II, however, differs slightly in chemical composition due to the
presence of terminal peptide constituents in its collagen [39]. Particular to vitreous and cartilage is an
acidic glycoprotein with a five-armed configuration, cartilage oligomeric matrix protein [40]. Its function
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